CN106083708A - 2 aminopyrazole derivatives containing 2 pyridone ring side chains and preparation and application - Google Patents

2 aminopyrazole derivatives containing 2 pyridone ring side chains and preparation and application Download PDF

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CN106083708A
CN106083708A CN201610529002.9A CN201610529002A CN106083708A CN 106083708 A CN106083708 A CN 106083708A CN 201610529002 A CN201610529002 A CN 201610529002A CN 106083708 A CN106083708 A CN 106083708A
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bis
pyridine
amino
compound
fluorophenyl
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郭晓
陈文腾
张璨
刘星雨
舒可
邵加安
俞永平
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Zhejiang University ZJU
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Zhejiang University ZJU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides a kind of 2 aminopyrazole derivatives containing 2 pyridone ring side chains or its enantiomer, mainly with 2 aminopyridines as parent nucleus, by obtaining target compound with 4 bromo 2 pyridone ring couplings.Experiment proves, tumor cell Karpas299 (NPM ALK positive cell strain), NCI H2228 (EML4 ALK positive cell strain), SKN BE2 (ALK gene amplifying cells strain) and the SH SY5Y (ALK F1174 mutant clone) relevant to alk tyrosine kinase activity at cellular level pair have significant inhibited proliferation, can prepare corresponding antitumor cell medicine.General structure I is:

Description

PA derivant containing 2-pyridone ring side chain and preparation and application
Technical field
The invention belongs to pharmaceutical field, be specifically related to a kind of PA derivant containing 2-pyridone ring side chain, with And preparation method and application.
Background technology
Anaplastic lymphoma kinase (ALK), i.e. anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase, is that one is under the jurisdiction of insulin The receptor tyrosine kinase of receptor superfamily.1994 by Morris and Shiota etc. from primary cutaneous type With the form (NPM-ALK) merging oncogene of a kind of activation in (Anaplastic large cell lymphoma, ALCL) Being found that ALK, continuous print research subsequently is found that the fusion form of multiple ALK in kinds cancer, including non-small cell Pulmonary carcinoma, inflammatory myofibroblasts tumor, diffusivity large B cell lymphoma etc..Complete ALK gene has typical receptor cheese ammonia The feature of acid kinase, comprises an extracellular region, a hydrophobic trans-membrane region and the kinases district of an intracellular.ALK is raw with cell Grow, breed, migrate closely bound up.Recent years, ALK inhibitor is developed rapidly in oncotherapy, but on early stage The Crizotinib of the medicine in city such as Pfizer research and development, initially treats effective patient and there will be drug resistance phenomenon at 6-12 month, Result display patient's drug resistance major part is owing to the site mutation on ALK have impact on the knot of drug molecule and alk tyrosine kinase Close affinity.Therefore, lot of domestic and foreign drugmaker accelerates the research and development paces of new A LK inhibitor.Novartis company grinds The Alectinib of Ceritinib and the Chugai/Roche company research and development sent out successively is criticized in April, 2014 and in July, 2014 Quasi-listing, the research and development for new A LK inhibitor have played a good impetus.
Summary of the invention
It is an object of the invention to provide a kind of PA derivant containing 2-pyridone ring side chain or its enantiomerism Body, has a following general structure I:
Wherein:
R1Selected from hydrogen, C1～C6Alkyl, C3～C6Ester group, C2～C6Chain amino, C1～C2The substituted C of alkyl2～C6Chain amino, The substituted C of tertbutyloxycarbonyl2～C6Chain amino；
R2For hydrogen, methyl；
R3For replacing or unsubstituted phenyl and substituted or unsubstituted heteroaryl, described is substituted by by C1～C6 Alkyl, halogen, C1～C6One or more in alkyl oxy, cyano group, trifluoromethyl are replaced；
X takes from hydrogen, oxygen, sulfur or amide.
PA derivant containing 2-pyridone ring side chain of the present invention or its corresponding isomer are following appointing One compound:
6-amino-[3,4'-bis-pyridine]-2'(1'H)-one (compound 1)；
6-amino-1'-methyl-[3,4'-bis-pyridine]-2'(1'H)-one (compound 2)；
6-amino-1'-benzyl-[3,4'-bis-pyridine]-2'(1'H)-one (compound 3)；
6-amino-1'-(2-(dimethylamino) ethyl)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 4)；
6-amino-5-(benzyloxy)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 5)；
6-amino-5-(benzyloxy)-1'-methyl-[3,4'-bis-pyridine]-2'(1'H)-one (compound 6)；
6-amino-5-(benzyloxy)-1'-benzyl-[3,4'-bis-pyridine]-2'(1'H)-one (compound 7)；
6-amino-5-(benzyloxy)-1'-(2-(dimethylamino) ethyl)-[3,4'-bis-pyridine]-2'(1'H)-one (change Compound 8)；
6-amino-5-((2,6-difluorobenzyl) oxo)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 9)；
6-amino-5-((2,6-difluorobenzyl) oxo)-1'-methyl-[3,4'-bis-pyridine]-2'(1'H)-one (compound 10)；
6-amino-5-((2,6-difluorobenzyl) oxo)-1'-benzyl-[3,4'-bis-pyridine]-2'(1'H)-one (compound 11)；
6-amino-5-((2,6-difluorobenzyl) oxo)-1'-(2-(dimethylamino) ethyl)-[3,4'-bis-pyridine]- 2'(1'H)-one (compound 12)；
6-amino-5-(1-phenyl ethoxy)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 13)；
6-amino-1'-methyl-5-(1-phenyl ethoxy)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 14)；
6-amino-5-(1-(p-methylphenyl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 15)；
6-amino-1'-methyl-5-(1-(p-methylphenyl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)-one (chemical combination Thing 16)；
6-amino-5-(1-(4-chlorphenyl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 17)；
6-amino-1'-methyl-5-(1-(4-chlorphenyl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 18)；
6-amino-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)-one (chemical combination Thing 19)；
6-amino-1'-methyl-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)- Ketone (compound 20)；
6-amino-1'-benzyl-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)- Ketone (compound 21)；
6-amino-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-1'-(2-(dimethylamino) ethyoxyl)-[3, 4'-bis-pyridine]-2'(1'H)-one (compound 22)；
6-amino-1'-methyl-5-(1-pyridine-2-base) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 23)；
6-amino-1'-methyl-5-(1-pyridin-3-yl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 24)；
6-amino-1'-methyl-5-(1-pyridin-4-yl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 25)；
(R)-6-amino-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 26)；
(R)-6-amino-1'-methyl-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis-pyridine]-2' (1'H)-one (compound 27)；
(R)-6-amino-1'-benzyl-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis-pyridine]-2' (1'H)-one (compound 28)；
(R)-6-amino-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-1'-(2-(dimethylamino) ethyoxyl)- [3,4'-bis-pyridine]-2'(1'H)-one (compound 29)；
(R)-6-amino-1'-ethyl-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis-pyridine]-2' (1'H)-one (compound 30)；
Ethyl-(R)-2-(6-amino-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-2'-epoxide-[3,4'-bis-pyrrole Pyridine]-1'(2'H)-yl) acetas (compound 31)；
(R)-6-amino-1'-propyl group-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis-pyridine]-2' (1'H)-one (compound 32)；
6-Amino-N-benzyl-2'-Oxy-1 ', 2'-dihydro-[3,4'-bis-pyridine]-5-Methanamide (compound 33)；
6-Amino-N-benzyl-1'-methyl-2'-Oxy-1 ', 2'-dihydro-[3,4'-bis-pyridine]-5-Methanamide (chemical combination Thing 34)；
6-amino-N, 1' dibenzyl-2'-Oxy-1 ', 2'-dihydro-[3,4'-bis-pyridine]-5-Methanamide (compound 35)；
6-amino-N-(2,6-difluorobenzyl)-2'-Oxy-1 ', 2'-dihydro-[3,4'-bis-pyridine]-5-Methanamide (is changed Compound 36)；
6-amino-N-(4-methoxyphenyl)-2'-Oxy-1 ', 2'-dihydro-[3,4'-bis-pyridine]-5-Methanamide (is changed Compound 37)；
6-amino-2'-epoxide-N-phenyl-1', 2'-dihydro-[3,4'-bis-pyridine]-5-Methanamide (compound 38)；
6-amino-N-(4-fluorophenyl)-2'-Oxy-1 ', 2'-dihydro-[3,4'-bis-pyridine]-5-Methanamide (compound 39)；
6-amino-2'-epoxide-N-(1-phenylethyl)-1', 2'-dihydro-[3,4'-bis-pyridine]-5-Methanamide (chemical combination Thing 40)；
6-amino-1'-methyl-2'-epoxide-(1-phenylethyl)-1', 2'-dihydro-[3,4'-bis-pyridine]-5-Methanamide (compound 41)；
6-amino-1'-benzyl-2'-epoxide-N-(1-phenylethyl)-1', 2'-dihydro-[3,4'-bis-pyridine]-5-formyl Amine (compound 42)；
6-amino-N-(1-(2,6-bis-chloro-3-fluorophenyl) ethyl)-2'-Oxy-1 ', 2'-dihydro-[3,4'-bis-pyrrole Pyridine]-5-Methanamide (compound 43)；
6-amino-N-(1-(2,6-bis-chloro-3-fluorophenyl) ethyl)-1'-methyl-2'-Oxy-1 ', 2'-dihydro-[3, 4'-bis-pyridine]-5-Methanamide (compound 44)；
6-amino-1'-benzyl-N-(1-(2,6-bis-chloro-3-fluorophenyl) ethyl)-2'-Oxy-1 ', 2'-dihydro-[3, 4'-bis-pyridine]-5-Methanamide (compound 45)；
(R)-6-amino-5-((1-(2,6-bis-chloro-3-fluorophenyl) ethyl) sulfenyl)-[3,4'-bis-pyridine]-2'(1'H)- Ketone (compound 46)；
(R)-6-amino-5-((1-(2,6-bis-chloro-3-fluorophenyl) ethyl) sulfenyl)-1'-methyl [3,4'-bis-pyridine]- 2'(1'H)-one (compound 47)；
(R)-6-amino-1'-benzyl-5-((1-(2,6-bis-chloro-3-fluorophenyl) ethyl) sulfenyl)-[3,4'-bis-pyridine]- 2'(1'H)-one (compound 48)；
(R)-6-amino-5-((1-(2,6-bis-chloro-3-fluorophenyl) ethyl) sulfenyl)-1'-(2-(dimethylamino) second Base)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 49)；
Ethyl (R)-2-(6-amino-5-((1-(2,6-bis-chloro-3-fluorophenyl) ethyl) sulfenyl)-2'-epoxide-[3,4'- Pyridine]-1'(2'H)-yl) acetas (compound 50)；
(R)-6-amino-5-((1-(2,6-bis-chloro-3-fluorophenyl) ethyl) sulfenyl)-1'-ethyl-[3,4'-bis-pyridine]- 2'(1'H)-one (compound 51)；
The tert-butyl group-(R)-(2-(6-amino-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-2'-oxygen-[3,4'-bis- Pyridine]-1'(2'H)-yl) ethyl) carboxylate (compound 52)；
(R)-6-amino-1'-(2-amino-ethyl)-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis-pyrrole Pyridine]-2'(1'H)-one (compound 53).
It is a further object to provide the described PA derivant containing 2-pyridone ring side chain or its The preparation method of corresponding isomer, is realized by following steps:
(1) prepared by compound A: under condition of ice bath, and raw material PA I and ammonium acetate stir 10min in acetonitrile, Then it is dividedly in some parts NBS (N-bromosuccinimide), is stirred under the same conditions half an hour, just obtaining after NBS adds Bromination product 5-bromo-PA II.Under anhydrous and oxygen-free operating condition, 5-bromo-PA II and connection boric acid frequency That alcohol ester and potassium acetate occur boration effect to generate (6-aminopyridine-3-base) boric acid under palladium catalyst catalytic action, This product can separate, and after LC-MS instrument (LC-MS) monitoring reaction terminates, uses " one kettle way ", directly to reactant System puts into the intermediate 2-pyridone III containing substituent group and appropriate palladium catalyst and cesium carbonate, and 110 DEG C are stirred overnight, finally Obtain target compound A.Reaction equation:
Wherein the definition of substituent group is with general structure I, reagent and reaction condition: a) acetonitrile, 0 DEG C, 0.5h；B) 1,4-dioxy Six rings, 80 DEG C；C) Isosorbide-5-Nitrae-dioxane, 110 DEG C, 10h；
(2) prepared by compound B: with 1-Phenylethanone. IV as initiation material, with methanol as solvent, repeatedly divides on a small quantity under condition of ice bath Criticize and add sodium borohydride, be then gradually brought to room temperature, after reaction 2h, generate 1-phenethanol V.Under condition of ice bath, by 1-benzene second Alcohol V is dissolved in dry oxolane, is subsequently added 2-hydroxy-3-nitropyridine VI and triphenylphosphine, then carries out nitrogen guarantor Protecting, azodiisobutyronitrile (DEAD) is dropwise slowly added in reaction system, drips complete rear chamber temperature and is stirred overnight, obtains 2-nitre Base-3-(1-ethoxyphenyl) pyridine VII.2-nitro-3-(1-ethoxyphenyl) pyridine VII obtains 3-(1-ethoxy through iron powder reducing Phenyl) pyridine-2-amine VIII.3-(1-ethoxyphenyl) pyridine-2-amine VIII generates through NBS (N-bromosuccinimide) bromo The bromo-3-of 5-(1-ethoxyphenyl) pyridine-2-amine IX.Under anhydrous and oxygen-free operating condition, the bromo-3-of 5-(1-ethoxyphenyl) pyridine- 2-amine IX occurs boration effect to generate (6-ammonia with connection boric acid pinacol ester and potassium acetate under palladium catalyst catalytic action Base-5-(1-ethoxyphenyl) pyridin-3-yl) boric acid, this product can separate, after LC-MS monitoring reaction terminates, we Use " one kettle way ", directly put into the 2-pyridone III containing substituent group and appropriate palladium catalyst and cesium carbonate to reaction system, 110 DEG C are stirred overnight, and have finally given target compound B.Reaction equation:
Wherein the definition of substituent group is with general structure I, reagent and reaction condition: a) methanol, 0 DEG C-room temperature, 2h；B) tetrahydrochysene Furan, 0 DEG C, 4h；C) ethanol, backflow, 1h, d) acetonitrile, 0 DEG C, 15min；E) Isosorbide-5-Nitrae-dioxane, 110 DEG C, 8h；F) 1,4-bis- Oxygen six ring, 110 DEG C, 10h.
(3) prepared by compound C: under condition of ice bath, and 1-phenethanol V and triethylamine are dissolved in dry dichloromethane, first Sulfonic acid chloride is added dropwise over, and progressively recovers to room temperature, be then stirred overnight and obtain 1-phenethyl first after treating mesyl chloride dropping Sulphonic acid ester X.1-phenethyl methanesulfonates X obtains (1-azidoethyl) benzene XI through Azide.(1-azidoethyl) benzene XI is at zinc powder Effect is lower occurs reduction to obtain 1-phenethylamine XII.At 2-, (7-aoxidizes benzo three nitrogen to 1-phenethylamine XII with 2-amino-5-bromo-nicotinic acid Azoles)-N, under N, N', N'-tetramethylurea hexafluorophosphoric acid ester (HATU) and DIPEA (DIPEA) act on, at N, N- Dimethylformamide (DMF) occur condensation reaction generate the 2-bromo-N-of amino-5-(1-phenethyl) nicotiamide XIII.Anhydrous Under oxygen free condition, the bromo-N-of 2-amino-5-(1-phenethyl) nicotiamide XIII, potassium acetate and connection boric acid pinacol ester are at palladium chtalyst There is boration reaction under agent catalytic action, generate (6-amino-5-((1-phenethyl) carbamyl) pyridin-3-yl) boron Acid, this product can separate, and we use " one kettle way ", after LC-MS monitoring reaction completes, directly throws to reaction system Entering intermediate 2-pyridone III and appropriate palladium catalyst and cesium carbonate, 110 DEG C are stirred overnight, and have finally given target chemical combination Thing C.Reaction equation:
Wherein the definition of substituent group is with general structure I, reagent and reaction condition: a) dichloromethane, 0 DEG C-room temperature, 10h；b) DMF, 50 DEG C, 8h；C) volume ratio is the ethanol/water of 3:1, room temperature, 3h, d) DMF, 0 DEG C, room temperature, 8h；E) Isosorbide-5-Nitrae-dioxane, 80 DEG C, 8h；F) Isosorbide-5-Nitrae-dioxane, 100 DEG C, 10h.
(4) prepared by compound D: at ambient temperature, and 2-nitro-3-pyridone VI and dimethylamino sulfur acute pyogenic infection of nails acyl chlorides exist O-(2-nitropyridine-3-base)-dimethyl thio ammonia is generated under the effect of 1,4-diazabicylo [2.2.2] octane (DABCO) Carbamate XIV.Solvent is made, O-(2-nitropyridine-3-base)-dimethyl thio amino under 160 DEG C of hot conditionss with diphenyl ether Formic acid esters XIV becomes S-(2-nitropyridine-3-base)-dimethylthiocarbamate XV.S-(2-nitropyridine-3-base)- Dimethylthiocarbamate XV occurs substitution reaction to generate 2-nitro-3-((1-phenethyl) sulfur under 1-phenethanol effect Generation) pyridine XVI.2-nitro-3-((1-phenethyl) sulfur generation) pyridine XVI generates 3-((1-phenethyl) sulfur generation) through iron powder reducing Pyridine-2-amine XVII, 3-((1-phenethyl) sulfur generation) pyridine-2-amine XVII generates the bromo-3-of 5-((1-phenethyl) sulfur through bromo Generation) pyridine-2-amine XVIII.The bromo-3-of 5-((1-phenethyl) sulfur generation) pyridine-2-amine XVIII, acetic acid under the conditions of anhydrous and oxygen-free Potassium occurs boration to react with connection boric acid pinacol ester under palladium catalyst catalytic action, generates (6-amino-5-((1-benzene second Base) sulfur generation) pyridin-3-yl) boric acid, this product can separate, and we use " one kettle way ", treats that LC-MS monitoring has been reacted Cheng Hou, directly puts into intermediate 2-pyridone III and appropriate palladium catalyst and cesium carbonate to reaction system, and 110 DEG C stirred At night, finally give target compound D.Reaction equation:
Reagent and reaction condition: a) DMF, room temperature, 24h；B) 160 DEG C, 3h；C) potassium hydroxide, volume Methanol/oxolane/water that ratio is 2:1:1,0 DEG C-room temperature；D) ethanol, backflow；E) bromine, potassium carbonate, dichloromethane, 0 DEG C； F) Isosorbide-5-Nitrae-dioxane, 80 DEG C, 8h；G) Isosorbide-5-Nitrae-dioxane, 110 DEG C, 10h.Wherein the definition of substituent group is with general structure I.
Raw material involved in preparation method of the present invention or intermediate, can directly buy, or mention according to embodiment part Literature method prepare.
Compound of formula I described in preparation method of the present invention, can be with organic synthesis and medicinal chemistry art and technology people Prepared by the multiple method known to Yuan, it is possible to use method described above prepares the compound of the present invention, it will be appreciated that When providing typical or preferred process condition (i.e. reaction temperature, time, the mol ratio of reactant, solvent, pressure etc. Deng), it is also possible to use other process conditions, except as otherwise noted.Optimum reaction condition can be with concrete reaction used Thing or solvent and change, but these conditions can be determined by routine optimization process by those skilled in the art.Generally, Reaction scheme as above and technique can be used to prepare the compounds of this invention, but the reagent being not limited in reaction condition and Solvent.
It is also another object of the present invention to provide the described PA derivant containing 2-pyridone ring side chain and Enantiomer application in preparing antitumor cell medicine.Described tumor cell refers at cellular level pair and ALK cheese ammonia (EML4-ALK is positive thin for tumor cell Karpas299 (NPM-ALK positive cell strain), the NCI-H2228 that kinase activity is relevant Born of the same parents' strain), SKN-BE2 (ALK gene amplifying cells strain) and SH-SY5Y (ALK F1174 mutant clone).It is demonstrated experimentally that Tumor cell Karpas299 (NPM-ALK positive cell strain), the NCI-that cellular level pair is relevant to alk tyrosine kinase activity (ALK F1174 suddenlys change for H2228 (EML4-ALK positive cell strain), SKN-BE2 (ALK gene amplifying cells strain) and SH-SY5Y Cell strain) there is significant inhibited proliferation, corresponding antitumor cell medicine can be prepared.
The invention provides the PA derivant that a class is brand-new, its pharmacodynamics embodiment experimental data shows, Tumor cell that cellular level pair is relevant to alk tyrosine kinase activity (Karpas299, NCI-H2228, SKN-BE2 and SH-SY5Y) there is significant inhibited proliferation, particularly cell strain Karpas299 is had preferable inhibition, for design New A LK inhibitor provides possibility.
Detailed description of the invention
Further illustrate the present invention below in conjunction with embodiment, but the most therefore limit the present invention to described embodiment model Among enclosing, the experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or according to description of commodity Book selects.
Embodiment 1:6-amino-[3,4'-bis-pyridine]-2'(1'H)-one (compound 1):
Step:
The bromo-PA of 5-(10.0mmol) and connection boric acid pinacol ester (11.0mmol) and potassium acetate (15.0mmol) It is dissolved in 20mL anhydrous dioxane, is subsequently adding Pd (dppf) Cl2(0.5mmol), nitrogen is replaced, 80 DEG C of heating 8h, LC-MS Monitoring reaction treats that raw material disappears.Question response natural cooling, does not separates, and adds cesium carbonate the most again in reaction system (15.0mmol)、Pd(dppf)Cl2(0.5mmol) with 4-bromopyridine-2 (1H)-one (11.0mmol), 0.5mL is then added Water, 110 DEG C are stirred overnight.Question response terminates, and reaction system kieselguhr filters, and filtrate is spin-dried for, then extracts with DCM.Close And organic facies, then anhydrous Na2SO4Being dried, filter, rotation is steamed, and crude product silica gel column chromatography separates (DCM:MeOH=20:1), To 6-amino-[3,4'-bis-pyridine]-2'(1'H)-one, yellow solid, productivity 72%.m.p.187-189℃；1H NMR (500MHz, DMSO) δ 11.45 (s, 1H), 8.31 (d, J=1.8Hz, 1H), 7.74 (dd, J=8.7,2.3Hz, 1H), 7.36 (d, J=6.7Hz, 1H), 6.49 (dd, J=14.9,8.7Hz, 3H), 6.36 (s, 2H)；HRMS(ESI):m/z calcd for C10H9N3O[M+H]+:188.0818,Found:188.0816.
Embodiment 2:6-amino-1'-methyl-[3,4'-bis-pyridine]-2'(1'H)-one
With reference to the method for embodiment 1, simply raw material 4-bromopyridine-2 (1H)-one is changed into 4-bromo-1-methyl-2 (1H)- Ketone, after reaction terminates, is evaporated to dry obtain crude product, obtains yellow solid through column chromatography purification (DCM/MeOH=10:1), Yield is 68%.
m.p.233-236℃；1H NMR (500MHz, DMSO) δ 8.32 (d, J=2.3Hz, 1H), 7.74 (dd, J=8.7, 2.6Hz, 1H), 7.66 (d, J=7.1Hz, 1H), 6.55 (d, J=1.9Hz, 1H), 6.52 (dd, J=7.1,2.1Hz, 1H), 6.50–6.45(m,1H),6.36(s,2H),3.39(s,3H)；HRMS(ESI):m/z calcd for C11H11N3O[M+H]+: 202.0975,Found:202.0976.m.p.>250℃；
Embodiment 3:6-amino-1'-benzyl-[3,4'-bis-pyridine]-2'(1'H)-one
With reference to the method for embodiment 1, simply raw material 4-bromopyridine-2 (1H)-one is changed into bromo-2 (1H) of 1-benzyl-4-- Ketone, after reaction terminates, is evaporated to dry obtain crude product, obtains white solid through column chromatography purification (DCM/MeOH=10:1), Yield is 60%.
m.p.207-209℃；1H NMR (500MHz, DMSO) δ 8.33 (s, 1H), 7.75 (dd, J=10.2,4.5Hz, 2H), 7.38 7.20 (m, 5H), 6.65 6.54 (m, 2H), 6.48 (d, J=8.7Hz, 1H), 6.38 (s, 2H), 5.08 (s, 2H)；HRMS(ESI):m/z calcd for C17H15N3O[M+H]+:278.1288,Found:278.1288.
Embodiment 4:6-amino-1'-(2-(dimethylamino) ethyl)-[3,4'-bis-pyridine]-2'(1'H)-one
With reference to the method for embodiment 1 into, simply raw material 4-bromopyridine-2 (1H)-one is changed 4-bromo-1-(2-(dimethylamino Base) ethyl) pyridine-2 (1H)-one, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH= 10:1) obtaining yellow solid, yield is 57%.
m.p.219-220℃；1H NMR (500MHz, DMSO) δ 8.31 (d, J=2.3Hz, 1H), 7.75 (dd, J=8.5, 2.6Hz, 1H), 7.66 (d, J=7.1Hz, 1H), 6.55 (d, J=1.9Hz, 1H), 6.53 (dd, J=7.1,2.1Hz, 1H), 6.52 6.43 (m, 1H), 6.35 (s, 2H), 3.98 (t, J=6.2Hz, 2H), 2.61 (t, J=6.2Hz, 2H), 2.28 (s, 6H)；HRMS(ESI):m/z calcd for C14H18N4O[M+H]+:259.1553,Found:259.1563.
Embodiment 5:6-amino-5-(benzyloxy)-[3,4'-bis-pyridine]-2'(1'H)-one
3-(benzyloxy)-5-bromopyridine-2-amine (10.0mmol) and connection boric acid pinacol ester (10.0mmol) and potassium acetate (15.0mmol) it is dissolved in 20mL anhydrous dioxane, is subsequently adding Pd (dppf) Cl2(0.5mmol), nitrogen is replaced, and 80 DEG C add Hot 8h, LC-MS monitoring reaction treats that raw material disappears.Question response natural cooling, does not separates, and adds carbonic acid the most again in reaction system Caesium (15.0mmol), Pd (dppf) Cl2(0.5mmol) with 4-bromopyridine-2 (1H)-one (11.0mmol), then add 0.5mL water, 110 DEG C are stirred overnight.Question response terminates, and reaction system kieselguhr filters, and filtrate is spin-dried for, then extracts with DCM Take.Merge organic facies, then anhydrous Na2SO4Being dried, filter, rotation is steamed, the separation of crude product silica gel column chromatography (DCM:MeOH=20: 1), white solid, productivity 76% are obtained.
m.p.231-234℃；1H NMR (500MHz, DMSO) δ 11.40 (s, 1H), 7.94 (d, J=1.5Hz, 1H), 7.52 (d, J=7.3Hz, 2H), 7.45 7.36 (m, 3H), 7.36 7.26 (m, 2H), 6.54 (d, J=1.4Hz, 1H), 6.49 (dd, J=6.9,1.7Hz, 1H), 6.18 (s, 2H), 5.25 (s, 2H)；HRMS(ESI):m/z calcd for C17H15N3O2[M +H]+:294.1237,Found:294.1228.
Embodiment 6:6-amino-5-(benzyloxy)-1'-methyl-[3,4'-bis-pyridine]-2'(1'H)-one
With reference to the method for embodiment 5, simply change 4-bromopyridine-2 (1H)-one into 4-bromo-1-methyl-2 (1H)-one, instead After should terminating, it is evaporated to dry obtain crude product, obtains pale white solid, yield through column chromatography purification (DCM/MeOH=20:1) It is 70%.
m.p.215-216℃；1H NMR (500MHz, DMSO) δ 7.96 (d, J=1.6Hz, 1H), 7.66 (d, J= 7.1Hz, 1H), 7.52 (d, J=7.3Hz, 2H), 7.43 (d, J=1.6Hz, 1H), 7.38 (t, J=7.5Hz, 2H), 7.31 (t, J=7.3Hz, 1H), 6.63 (d, J=1.8Hz, 1H), 6.56 (dd, J=7.1,2.0Hz, 1H), 6.18 (s, 2H), 5.25 (s, 2H),3.39(s,3H)；HRMS(ESI):m/z calcd for C18H17N3O2[M+H]+:308.1394,Found: 308.1394.
Embodiment 7:6-amino-5-(benzyloxy)-1'-benzyl-[3,4'-bis-pyridine]-2'(1'H)-one
With reference to the method for embodiment 5, simply change 4-bromopyridine-2 (1H)-one into 1-benzyl-4-bromo-2 (1H)-one, instead After should terminating, it is evaporated to dry obtain crude product, obtains pale white solid, yield through column chromatography purification (DCM/MeOH=20:1) It is 58%.
m.p.174-176℃；1H NMR (500MHz, DMSO) δ 7.97 (d, J=1.8Hz, 1H), 7.76 (d, J= 7.2Hz, 1H), 7.52 (d, J=7.3Hz, 2H), 7.45 (d, J=1.7Hz, 1H), 7.38 (t, J=7.5Hz, 2H), 7.35 7.16 (m, 6H), 6.68 (d, J=1.9Hz, 1H), 6.61 (dd, J=7.2,2.0Hz, 1H), 6.22 (s, 2H), 5.25 (s, 2H),5.09(s,2H)；HRMS(ESI):m/z calcd for C24H21N3O2[M+H]+:384.1707,Found: 384.1709.
Embodiment 8:6-amino-5-(benzyloxy)-1'-(2-(dimethylamino) ethyl)-[3,4'-bis-pyridine]-2'(1' H)-one
With reference to the method for embodiment 5 into, simply 4-bromopyridine-2 (1H)-one is changed the bromo-1-of 4-(2-(dimethylamino) second Base) pyridine-2 (1H)-one, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH=20:1) Obtaining yellow solid, yield is 52%.
m.p.154-157℃；1H NMR (500MHz, DMSO) δ 7.98 (d, J=1.6Hz, 1H), 7.65 (d, J= 7.1Hz, 1H), 7.51 (d, J=7.3Hz, 2H), 7.42 (d, J=1.6Hz, 1H), 7.36 (t, J=7.5Hz, 2H), 7.32 (t, J=7.3Hz, 1H), 6.65 (d, J=1.8Hz, 1H), 6.55 (dd, J=7.1,2.0Hz, 1H), 6.18 (s, 2H), 5.25 (s, 2H), 3.96 (t, J=6.2Hz, 2H), 2.63 (t, J=6.2Hz, 2H), 2.27 (s, 6H)；HRMS(ESI):m/z calcd for C21H24N4O2[M+H]+:365.1972,Found:365.1968.
Embodiment 9:6-amino-5-((2,6-difluorobenzyl) oxo)-[3,4'-bis-pyridine]-2'(1'H)-one
With reference to the method for embodiment 5, simply change 3-(benzyloxy)-5-bromopyridine-2-amine into 5-bromo-3-((2,6-difluoros Benzyl) oxygen) pyridine-2-amine, after reaction terminates, be evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH=20: 1) obtaining white solid, yield is 66%.
m.p.214-216℃；1H NMR (500MHz, DMSO) δ 11.41 (s, 1H), 7.97 (d, J=1.9Hz, 1H), 7.64 7.47 (m, 2H), 7.35 (d, J=6.9Hz, 1H), 7.18 (t, J=8.0Hz, 2H), 6.60 (d, J=1.6Hz, 1H), 6.54 (dd, J=7.0,1.8Hz, 1H), 6.04 (s, 2H), 5.23 (s, 2H)；HRMS(ESI):m/z calcd for C17H13F2N3O2[M+H]+:330.1049,Found:330.1044.
Embodiment 10:6-amino-5-((2,6-difluorobenzyl) oxo)-1'-methyl-[3,4'-bis-pyridine]-2'(1'H)- Ketone
With reference to the method for embodiment 6, simply will simply 3-(benzyloxy)-5-bromopyridine-2-amine be changed into the bromo-3-of 5-((2, 6-difluorobenzyl) oxygen) pyridine-2-amine, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH =20:1) obtain black solid, yield is 70%.
m.p.174-176℃；1H NMR (500MHz, DMSO) δ 8.00 (d, J=1.7Hz, 1H), 7.68 (d, J= 7.1Hz, 1H), 7.59 7.48 (m, 2H), 7.18 (t, J=8.0Hz, 2H), 6.69 (d, J=1.9Hz, 1H), 6.60 (dd, J= 7.2,2.0Hz,1H),6.05(s,2H),5.24(s,2H),3.41(s,3H)；HRMS(ESI):m/z calcd for C18H15F2N3O2[M+H]+:344.1205,Found:344.1208.
Embodiment 11:6-amino-5-((2,6-difluorobenzyl) oxo)-1'-benzyl-[3,4'-bis-pyridine]-2'(1'H)- Ketone
With reference to the method for embodiment 7, simply change 3-(benzyloxy)-5-bromopyridine-2-amine into 5-bromo-3-((2,6-difluoros Benzyl) oxygen) pyridine-2-amine, after reaction terminates, be evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH=20: 1) obtaining yellow solid, yield is 50%.
m.p.169-172℃；1H NMR (500MHz, DMSO) δ 8.01 (d, J=1.8Hz, 1H), 7.78 (d, J= 7.2Hz, 1H), 7.58 (d, J=1.9Hz, 1H), 7.56 7.46 (m, 1H), 7.38 7.24 (m, 5H), 7.22 7.12 (m, 2H), 6.73 (d, J=2.0Hz, 1H), 6.65 (dd, J=7.2,2.1Hz, 1H), 6.07 (s, 2H), 5.23 (s, 2H), 5.10 (s,2H)；HRMS(ESI):m/z calcd for C24H19F2N3O2[M+H]+:420.1518,Found:420.1518.
Embodiment 12:6-amino-5-((2,6-difluorobenzyl) oxo)-1'-(2-(dimethylamino) ethyl)-[3,4'- Two pyridines]-2'(1'H)-one
With reference to the method for embodiment 8, simply change 3-(benzyloxy)-5-bromopyridine-2-amine into 5-bromo-3-((2,6-difluoros Benzyl) oxygen) pyridine-2-amine, after reaction terminates, be evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH=20: 1) obtaining yellow solid, yield is 47%.
m.p.69-71℃；1H NMR (500MHz, DMSO) δ 8.00 (s, 1H), 7.62 (d, J=7.2Hz, 1H), 7.57 (d, J=1.5Hz, 1H), 7.52 (ddd, J=15.1,8.3,6.8Hz, 1H), 7.18 (t, J=8.0Hz, 2H), 6.67 (d, J= 1.8Hz, 1H), 6.59 (dd, J=7.2,2.0Hz, 1H), 6.05 (s, 2H), 5.23 (s, 2H), 3.97 (t, J=6.3Hz, 2H), 2.54 (t, J=5.7Hz, 2H), 2.21 (s, 6H)；HRMS(ESI):m/z calcd for C21H22F2N4O2[M+H]+: 401.1784,Found:401.1782.
Embodiment 13:6-amino-5-(1-phenyl ethoxy)-[3,4'-bis-pyridine]-2'(1'H)-one
With reference to the method for embodiment 5, simply change 3-(benzyloxy)-5-bromopyridine-2-amine into the bromo-3-of 5-(1-phenyl second Epoxide) pyridine-2-amine, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH=20:1) To gray solid, yield is 71%.
m.p.231-233℃；1H NMR (500MHz, DMSO) δ 11.39 (s, 1H), 7.85 (d, J=1.6Hz, 1H), 7.48 (d, J=7.4Hz, 2H), 7.32 (dd, J=15.4,7.6Hz, 3H), 7.22 (dd, J=15.3,4.4Hz, 2H), 6.37 (d, J=4.8Hz, 2H), 6.24 (s, 2H), 5.73 (q, J=6.2Hz, 1H), 1.57 (d, J=6.3Hz, 3H)；HRMS(ESI): m/z calcd for C18H17N3O2[M+H]+:308.1394,Found:308.1394.
Embodiment 14:6-amino-1'-methyl-5-(1-phenyl ethoxy)-[3,4'-bis-pyridine]-2'(1'H)-one
With reference to the method for embodiment 6, simply simply 3-(benzyloxy)-5-bromopyridine-2-amine will be changed into 5-bromo-3-(1- Phenyl ethoxy) pyridine-2-amine, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH= 20:1) obtaining black solid, yield is 65%.
m.p.205-207℃；1H NMR (500MHz, DMSO) δ 7.87 (d, J=1.3Hz, 1H), 7.61 (d, J= 7.1Hz, 1H), 7.48 (d, J=7.4Hz, 2H), 7.32 (t, J=7.5Hz, 2H), 7.23 (dd, J=8.1,4.5Hz, 2H), 6.47 (d, J=1.5Hz, 1H), 6.46 6.37 (m, 1H), 6.25 (s, 2H), 5.74 (q, J=6.2Hz, 1H), 3.35 (s, 3H), 1.57 (d, J=6.3Hz, 3H)；HRMS(ESI):m/z calcd for C19H19N3O2[M+H]+:322.1550, Found:322.1554.
Embodiment 15:6-amino-5-(1-(p-methylphenyl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)-one
With reference to the method for embodiment 5, (1-is to methyl simply to change 3-(benzyloxy)-5-bromopyridine-2-amine into 5-bromo-3- Phenyl ethoxy) pyridine-2-amine, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH= 20:1) obtaining yellow solid, yield is 71%.
m.p.178.1-179.2℃；1H NMR(500MHz,DMSO)δ11.40(s,1H),7.88(s,1H),7.55(d,J =8.2Hz, 2H), 7.40 (d, J=8.2Hz, 2H), 7.33 (d, J=6.8Hz, 1H), 7.26 (s, 1H), 6.47 6.38 (m, 2H), 6.28 (s, 2H), 5.84 5.74 (m, 1H), 2.32 (s, 3H), 1.57 (d, J=6.3Hz, 3H)；HRMS(ESI):m/z calcd for C19H19N3O2[M+H]+:322.1550,Found:322.1552.
Embodiment 16:6-amino-1'-methyl-5-(1-(p-methylphenyl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1' H)-one
With reference to the method for embodiment 6, (1-is to methyl simply to change 3-(benzyloxy)-5-bromopyridine-2-amine into 5-bromo-3- Phenyl ethoxy) pyridine-2-amine, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH= 20:1) obtaining yellow solid, yield is 76%.
m.p.186-187℃；1H NMR(500MHz,CDCl3) δ 7.84 (s, 1H), 7.24 (t, J=7.1Hz, 3H), 7.16 (d, J=7.9Hz, 2H), 6.95 (d, J=1.3Hz, 1H), 6.52 (d, J=1.5Hz, 1H), 6.24 (d, J=7.0Hz, 1H), 5.33 (q, J=6.4Hz, 1H), 5.26 (s, 2H), 3.52 (s, 3H), 2.32 (s, 3H), 1.67 (d, J=6.4Hz, 3H)；HRMS (ESI):m/z calcd for C20H21N3O2[M+H]+:336.1707,Found:336.1702.
Embodiment 17:6-amino-5-(1-(4-chlorphenyl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)-one
With reference to the method for embodiment 5, simply change 3-(benzyloxy)-5-bromopyridine-2-amine into the bromo-3-of 5-(1-(4-chlorobenzene Base) ethyoxyl) pyridine-2-amine, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH= 20:1) obtaining black solid, yield is 62%.
m.p.189-192℃；1H NMR (500MHz, DMSO) δ 11.41 (s, 1H), 7.89 (s, 1H), 7.54 (d, J= 8.3Hz, 2H), 7.41 (d, J=8.3Hz, 2H), 7.33 (d, J=6.8Hz, 1H), 7.26 (s, 1H), 6.47-6.38 (m, 2H), 6.28 (s, 2H), 5.84 5.74 (m, 1H), 1.57 (d, J=6.3Hz, 3H)；HRMS(ESI):m/z calcd for C18H16ClN3O2[M+H]+:342.1004,Found:342.1001.
Embodiment 18:6-amino-1'-methyl-5-(1-(4-chlorphenyl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)- Ketone
With reference to the method for embodiment 6, simply change 3-(benzyloxy)-5-bromopyridine-2-amine into the bromo-3-of 5-(1-(4-chlorobenzene Base) ethyoxyl) pyridine-2-amine, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH= 20:1) obtaining gray solid, yield is 67%.
m.p.257-259℃；1H NMR(500MHz,CDCl3) δ 7.85 (d, J=1.1Hz, 1H), 7.33 (dd, J= 20.9,8.5Hz, 4H), 7.27 (d, J=7.1Hz, 1H), 6.92 (d, J=1.3Hz, 1H), 6.55 (d, J=1.5Hz, 1H), 6.26 (dd, J=7.0,1.7Hz, 1H), 5.36 (dd, J=12.6,6.1Hz, 3H), 3.55 (s, 3H), 1.69 (d, J= 6.4Hz,3H)；HRMS(ESI):m/z calcd for C19H18ClN3O2[M+H]+:356.1160,Found:356.1157.
Embodiment 19:6-amino-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1' H)-one
With reference to the method for embodiment 5, simply change 3-(benzyloxy)-5-bromopyridine-2-amine into the bromo-3-of 5-(1-(2,6-bis- Chloro-3-fluorophenyl) ethyoxyl) after the reaction of pyridine-2-amine terminates, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/ MeOH=20:1) obtaining yellow solid, yield is 71%.
m.p.250-252℃；1H NMR (500MHz, DMSO) δ 11.43 (s, 1H), 7.92 (d, J=1.8Hz, 1H), 7.57 (dd, J=9.0,4.9Hz, 1H), 7.46 (t, J=8.7Hz, 1H), 7.34 (d, J=6.9Hz, 1H), 6.94 (d, J= 1.6Hz, 1H), 6.32 (dd, J=6.9,1.7Hz, 1H), 6.27 (d, J=1.5Hz, 1H), 6.21 (s, 2H), 6.16 (t, J= 6.6Hz, 1H), 1.81 (d, J=6.6Hz, 3H)；HRMS(ESI):m/z calcd for C18H14Cl2FN3O2[M+H]+: 394.0520,Found:394.0516.
Embodiment 20:6-amino-1'-methyl-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis-pyrrole Pyridine]-2'(1'H)-one
With reference to the method for embodiment 6, simply change 3-(benzyloxy)-5-bromopyridine-2-amine into the bromo-3-of 5-(1-(2,6-bis- Chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH=20:1) obtaining yellow solid, yield is 78%.
m.p.130-133℃；1H NMR(500MHz,CDCl3) δ 7.92 (d, J=1.7Hz, 1H), 7.35 (dd, J=8.9, 4.8Hz, 1H), 7.09 (dd, J=8.8,8.0Hz, 1H), 6.99 (d, J=1.8Hz, 1H), 6.60 (d, J=2.0Hz, 1H), 6.27 (dd, J=7.1,2.1Hz, 1H), 6.13 (q, J=6.7Hz, 1H), 5.07 (d, J=23.9Hz, 2H), 3.56 (s, 3H), 1.88 (d, J=6.7Hz, 3H)；HRMS(ESI):m/z calcd for C19H16Cl2FN3O2[M+H]+:408.0676,Found: 408.0672.
Embodiment 21:6-amino-1'-benzyl-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis-pyrrole Pyridine]-2'(1'H)-one
With reference to the method for embodiment 7, simply change 3-(benzyloxy)-5-bromopyridine-2-amine into the bromo-3-of 5-(1-(2,6-bis- Chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH=20:1) obtaining yellow solid, yield is 62%.
m.p.89-91℃；1H NMR(500MHz,CDCl3) δ 7.93 (d, J=1.8Hz, 1H), 7.36 (tt, J=8.5, 6.0Hz, 6H), 7.27 (d, J=7.2Hz, 1H), 7.09 (dd, J=8.8,8.0Hz, 1H), 6.99 (d, J=1.8Hz, 1H), 6.64 (d, J=2.0Hz, 1H), 6.28 (dd, J=7.2,2.1Hz, 1H), 6.13 (q, J=6.7Hz, 1H), 5.17 (s, 2H), 5.06 (s, 2H), 1.88 (d, J=6.7Hz, 3H)；HRMS(ESI):m/z calcd for C25H20Cl2FN3O2[M+H]+: 484.0989,Found:484.0992.
Embodiment 22:6-amino-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-1'-(2-(dimethylamino) second Epoxide)-[3,4'-bis-pyridine]-2'(1'H)-one
With reference to the method for embodiment 8, simply change 3-(benzyloxy)-5-bromopyridine-2-amine into the bromo-3-of 5-(1-(2,6-bis- Chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH=20:1) obtaining black solid, yield is 57%.
m.p.224-227℃；1H NMR(500MHz,DMSO)δ7.94(s,1H),7.66–7.56(m,2H),7.43(t,J =8.6Hz, 1H), 6.92 (s, 1H), 6.35 (dd, J=23.1,16.1Hz, 2H), 6.21 (s, 2H), 6.17 (dd, J=12.9, 6.3Hz, 1H), 3.92 (t, J=5.9Hz, 2H), 2.48 (d, J=6.1Hz, 2H), 2.19 (s, 6H), 1.82 (d, J=6.5Hz, 3H)；HRMS(ESI):m/z calcd for C22H23Cl2FN4O2[M+H]+:465.1255,Found:465.1249.
Embodiment 23:6-amino-1'-methyl-5-(1-pyridine-2-base) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)- Ketone
With reference to the method for embodiment 6, simply 3-(benzyloxy)-5-bromopyridine-2-amine is changed into the bromo-3-of 5-(1-(pyridine- 2-yl) ethyoxyl) pyridine-2-amine, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH= 20:1) obtaining black solid, yield is 46%.
m.p.204-207℃；1H NMR (500MHz, DMSO) δ 8.53 (d, J=4.2Hz, 1H), 7.89 (d, J= 1.8Hz, 1H), 7.78 (td, J=7.7,1.6Hz, 1H), 7.62 (d, J=7.0Hz, 1H), 7.53 (d, J=7.9Hz, 1H), 7.28 (dd, J=6.6,4.9Hz, 1H), 7.20 (d, J=1.7Hz, 1H), 6.49 6.35 (m, 2H), 6.27 (s, 2H), 5.68 (q, J=6.4Hz, 1H), 3.37 (s, 3H), 1.61 (d, J=6.4Hz, 3H)；HRMS(ESI):m/z calcd for C18H18N4O2[M+H]+:323.1503,Found:323.1507.
Embodiment 24:6-amino-1'-methyl-5-(1-pyridin-3-yl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)- Ketone
With reference to the method for embodiment 6, simply 3-(benzyloxy)-5-bromopyridine-2-amine is changed into the bromo-3-of 5-(1-(pyridine- 3-yl) ethyoxyl) pyridine-2-amine, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH= 20:1) obtaining black solid, yield is 41%.
m.p.203-205℃；1H NMR(500MHz,DMSO)δ8.72(s,1H),8.54–8.38(m,1H),7.92 (ddd, J=8.6,5.2,1.9Hz, 2H), 7.63 (d, J=7.1Hz, 1H), 7.42 7.32 (m, 2H), 6.54 (d, J= 2.0Hz, 1H), 6.48 (dd, J=7.2,2.1Hz, 1H), 6.31 (s, 2H), 5.86 (q, J=6.3Hz, 1H), 3.39 (d, J= 10.3Hz, 3H), 1.59 (d, J=6.4Hz, 3H)；HRMS(ESI):m/z calcd for C18H18N4O2[M+H]+: 323.1503,Found:323.1510.
Embodiment 25:6-amino-1'-methyl-5-(1-pyridin-4-yl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)- Ketone
With reference to the method for embodiment 6, simply 3-(benzyloxy)-5-bromopyridine-2-amine is changed into the bromo-3-of 5-(1-(pyridine- 4-yl) ethyoxyl) pyridine-2-amine, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH= 20:1) obtaining yellow oil, yield is 38%.
1H NMR(500MHz,CDCl3) δ 8.61 (d, J=5.8Hz, 2H), 7.91 (d, J=1.6Hz, 1H), 7.28 (d, J =5.9Hz, 2H), 7.25 (d, J=7.2Hz, 1H), 6.85 (d, J=1.5Hz, 1H), 6.52 (d, J=1.7Hz, 1H), 6.22 (dd, J=7.1,1.9Hz, 1H), 5.36 (q, J=6.4Hz, 1H), 5.09 (s, 2H), 3.53 (s, 3H), 1.71 (d, J= 6.5Hz,3H)；HRMS(ESI):m/z calcd for C18H18N4O2[M+H]+:323.1503,Found:323.1500.
Embodiment 26:(R)-6-amino-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis-pyridine]-2' (1'H)-one is with reference to the method for embodiment 5, simply 3-(benzyloxy)-5-bromopyridine-2-amine is changed into the bromo-3-of (R)-5-(1-(2, 6-bis-chloro-3-fluorophenyl) ethyoxyl) after the reaction of pyridine-2-amine terminates, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH=20:1) obtaining yellow solid, yield is 71%.
m.p.265-267℃；1H NMR (500MHz, DMSO) δ 11.44 (s, 1H), 7.92 (s, 1H), 7.57 (dd, J= 8.9,4.9Hz, 1H), 7.45 (t, J=8.7Hz, 1H), 7.35 (d, J=6.9Hz, 1H), 6.94 (s, 1H), 6.35 6.30 (m, 1H), 6.28 (s, 1H), 6.22 (s, 2H), 6.15 (q, J=6.5Hz, 1H), 1.81 (d, J=6.6Hz, 3H)；HRMS(ESI): m/z calcd for C18H14Cl2FN3O2[M+H]+:394.0520,Found:394.0527.
Embodiment 27:(R)-6-amino-1'-methyl-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis- Pyridine]-2'(1'H)-one
With reference to the method for embodiment 6, simply 3-(benzyloxy)-5-bromopyridine-2-amine is changed into the bromo-3-of (R)-5-(1-(2, 6-bis-chloro-3-fluorophenyl) ethyoxyl) after the reaction of pyridine-2-amine terminates, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH=20:1) obtaining yellow solid, yield is 75%.
m.p.109-111℃；1H NMR (500MHz, DMSO) δ 7.94 (s, 1H), 7.66 (d, J=6.8Hz, 1H), 7.57 (dd, J=8.8,4.8Hz, 1H), 7.46 (t, J=8.6Hz, 1H), 6.95 (s, 1H), 6.37 (d, J=6.5Hz, 2H), 6.21 (s, 2H), 6.18 6.01 (m, 1H), 3.39 (s, 3H), 1.81 (d, J=6.5Hz, 3H)；HRMS(ESI):m/z calcd for C19H16Cl2FN3O2[M+H]+:408.0676,Found:408.0672.
Embodiment 28:(R)-6-amino-1'-benzyl-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis- Pyridine]-2'(1'H)-one
With reference to the method for embodiment 7, simply 3-(benzyloxy)-5-bromopyridine-2-amine is changed into the bromo-3-of (R)-5-(1-(2, 6-bis-chloro-3-fluorophenyl) ethyoxyl) after the reaction of pyridine-2-amine terminates, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH=20:1) obtaining yellow solid, yield is 65%.
m.p.112-114℃；1H NMR (500MHz, DMSO) δ 7.96 (s, 1H), 7.77 (d, J=7.1Hz, 1H), 7.57 (dd, J=8.9,4.9Hz, 1H), 7.45 (t, J=8.7Hz, 1H), 7.37 7.27 (m, 5H), 6.97 (s, 1H), 6.43 (d, J =7.2Hz, 1H), 6.40 (s, 1H), 6.25 (s, 2H), 6.16 (q, J=6.5Hz, 1H), 5.07 (s, 2H), 1.81 (d, J= 6.6Hz,3H).13C NMR(125MHz,DMSO)δ161.9,152.7,148.8,139.3,139.0,138.7,138.0, 137.1,131.0,129.2,129.0,128.2,128.0,120.4,118.0,117.9,114.6,113.0,103.7,72.6, 56.5,51.1,19.1；HRMS(ESI):m/z calcd for C25H20Cl2FN3O2[M+H]+:484.0989,Found: 484.0987.
Embodiment 29:(R)-6-amino-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-1'-(2-(dimethylamino Base) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)-one
With reference to the method for embodiment 8, simply 3-(benzyloxy)-5-bromopyridine-2-amine is changed into the bromo-3-of (R)-5-(1-(2, 6-bis-chloro-3-fluorophenyl) ethyoxyl) after the reaction of pyridine-2-amine terminates, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH=20:1) obtaining yellow solid, yield is 53%.
m.p.198-201℃；1H NMR(500MHz,DMSO)δ7.95(s,1H),7.65–7.54(m,2H),7.45(t,J =8.6Hz, 1H), 6.95 (s, 1H), 6.37 (dd, J=23.1,16.1Hz, 2H), 6.22 (s, 2H), 6.15 (dd, J=12.9, 6.3Hz, 1H), 3.93 (t, J=5.9Hz, 2H), 2.49 (d, J=6.1Hz, 2H), 2.18 (s, 6H), 1.81 (d, J=6.5Hz, 3H)；HRMS(ESI):m/z calcd for C22H23Cl2FN4O2[M+H]+:465.1255,Found:465.1258.
Embodiment 30:(R)-6-amino-1'-ethyl-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis- Pyridine]-2'(1'H)-one
With reference to the method for embodiment 5, simply 3-(benzyloxy)-5-bromopyridine-2-amine is changed into the bromo-3-of (R)-5-(1-(2, 6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine, 4-bromopyridine-2 (1H)-one is changed into 4-bromo-1-ethyl-2 (1H)-one After reaction terminates, it is evaporated to dry obtain crude product, obtains white solid, yield through column chromatography purification (DCM/MeOH=20:1) It is 66%.
m.p.184-186℃；1H NMR (500MHz, DMSO) δ 7.91 (d, J=1.9Hz, 1H), 7.69 7.62 (m, 1H), 7.55 (dd, J=9.0,4.9Hz, 1H), 7.44 (t, J=8.7Hz, 1H), 6.92 (d, J=1.9Hz, 1H), 6.36 (dd, J=7.2,2.1Hz, 1H), 6.32 (d, J=2.0Hz, 1H), 6.21 (s, 2H), 6.13 (q, J=6.6Hz, 1H), 3.85 (q, J =7.1Hz, 2H), 1.18 (t, J=7.1Hz, 3H)；HRMS(ESI):m/z calcd for C20H18Cl2FN3O2[M+H]+: 422.0833,Found:422.0831.
Embodiment 31: ethyl-(R)-2-(6-amino-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-2'-epoxide- [3,4'-bis-pyridine]-1'(2'H)-yl) acetas
With reference to the method for embodiment 5, simply 3-(benzyloxy)-5-bromopyridine-2-amine is changed into the bromo-3-of (R)-5-(1-(2, 6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine, 4-bromopyridine-2 (1H)-one is changed into ethyl 2-(4-bromo-2-epoxide pyrrole Pyridine-1 (2H)-yl) acetas, after reaction terminates, be evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH=20: 1) obtaining yellow solid, yield is 57%.
m.p.142-145℃；1H NMR (500MHz, DMSO) δ 7.95 (d, J=1.7Hz, 1H), 7.63 (d, J= 7.2Hz, 1H), 7.55 (dd, J=8.9,4.9Hz, 1H), 7.43 (t, J=8.7Hz, 1H), 6.94 (d, J=1.5Hz, 1H), 6.43 (dd, J=7.2,1.9Hz, 1H), 6.36 (d, J=1.8Hz, 1H), 6.26 (s, 2H), 6.14 (q, J=6.6Hz, 1H), 4.63 (s, 2H), 4.12 (q, J=7.1Hz, 2H), 1.79 (d, J=6.6Hz, 3H), 1.19 (t, J=7.1Hz, 3H)；HRMS (ESI):m/z calcd for C22H20Cl2FN3O4[M+H]+:480.0888,Found:480.0882.
Embodiment 32:(R)-6-amino-1'-propyl group-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis- Pyridine]-2'(1'H)-one
With reference to the method for embodiment 5, simply 3-(benzyloxy)-5-bromopyridine-2-amine is changed into the bromo-3-of (R)-5-(1-(2, 6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine, 4-bromopyridine-2 (1H)-one is changed into 4-bromo-1-propyl group-2 (1H)-one After reaction terminates, it is evaporated to dry obtain crude product, obtains yellow solid, yield through column chromatography purification (DCM/MeOH=20:1) It is 68%.
m.p.157-159℃；1H NMR (500MHz, DMSO) δ 7.92 (d, J=1.8Hz, 1H), 7.62 (d, J= 7.1Hz, 1H), 7.54 (dd, J=8.9,4.9Hz, 1H), 7.42 (t, J=8.7Hz, 1H), 6.92 (d, J=1.8Hz, 1H), 6.38 6.30 (m, 2H), 6.21 (s, 2H), 6.12 (q, J=6.6Hz, 1H), 3.81 3.70 (m, 2H), 1.78 (d, J= 6.6Hz, 3H), 1.61 (dt, J=14.6,7.3Hz, 2H), 0.83 (t, J=7.4Hz, 3H)；HRMS(ESI):m/z calcd for C21H20Cl2FN3O2[M+H]+:436.0989,Found:436.0989.
Embodiment 33: the tert-butyl group-(R)-(2-(6-amino-5-(1-(2,6-bis-chloro-3-fluorine) ethyoxyl)-2'-oxygen-[3, 4'-bis-pyridine]-1'(2'H)-yl) ethyl) carboxylate
With reference to the method for embodiment 5, simply 3-(benzyloxy)-5-bromopyridine-2-amine is changed into the bromo-3-of (R)-5-(1-(2, 6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine, 4-bromopyridine-2 (1H)-one is changed into the tert-butyl group (2-(4-bromo-2-epoxide Pyridine-1 (2H)-yl) ethyl) carboxylate, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/ MeOH=20:1) obtaining yellow solid, yield is 56%.
1H NMR(500MHz,CDCl3) δ 7.88 (s, 1H), 7.32 (dd, J=8.9,4.8Hz, 1H), 7.24 (d, J= 7.0Hz, 1H), 7.12 7.03 (m, 1H), 6.95 (s, 1H), 6.53 (dd, J=21.6,1.8Hz, 1H), 6.26 (d, J= 6.5Hz, 1H), 6.10 (q, J=6.7Hz, 1H), 5.16 (s, 2H), 5.11 (s, 1H), 4.08 (t, J=5.8Hz, 2H), 3.47 (q, J=5.9Hz, 2H), 1.86 (d, J=6.7Hz, 3H), 1.42 (s, 9H)；HRMS(ESI):m/z calcd for C25H27Cl2FN4O4[M+H]+:537.1466,Found:537.1466.
Embodiment 34:(R)-6-amino-1'-(2-amino-ethyl)-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)- [3,4'-bis-pyridine]-2'(1'H)-one
With reference to the method for embodiment 5, simply 3-(benzyloxy)-5-bromopyridine-2-amine is changed into the bromo-3-of (R)-5-(1-(2, 6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine, 4-bromopyridine-2 (1H)-one is changed into 1-(2-amino-ethyl)-4-bromine pyrrole Pyridine-2 (1H)-one, after reaction terminates, is evaporated to dry obtain crude product, obtains through column chromatography purification (DCM/MeOH=20:1) Yellow liquid, yield is 47%.
1H NMR (500MHz, DMSO) δ 7.93 (d, J=1.7Hz, 1H), 7.60 (d, J=7.1Hz, 1H), 7.55 (dd, J =8.9,4.9Hz, 1H), 7.44 (t, J=8.7Hz, 1H), 6.92 (d, J=1.4Hz, 1H), 6.39 (dd, J=7.2,1.9Hz, 1H), 6.34 (t, J=5.7Hz, 1H), 6.23 (s, 2H), 6.13 (q, J=6.5Hz, 1H), 3.90 (t, J=6.1Hz, 2H), 2.89 (t, J=6.1Hz, 2H), 1.79 (d, J=6.6Hz, 3H)；HRMS(ESI):m/z calcd for C20H21Cl2FN4O2 [M+H]+:437.0942,Found:437.0940.
Embodiment 35:6-Amino-N-benzyl-2'-Oxy-1 ', 2'-dihydro-[3,4'-bis-pyridine]-5-Methanamide
2-Amino-N-benzyl-5-bromine nicotiamide and connection boric acid pinacol ester (11.0mmol) and potassium acetate (15.0mmol) It is dissolved in 20mL anhydrous dioxane, is subsequently adding Pd (dppf) Cl2(0.5mmol), nitrogen is replaced, 80 DEG C of heating 8h, LC-MS Monitoring reaction treats that raw material disappears.Question response natural cooling, does not separates, and adds cesium carbonate the most again in reaction system (15.0mmol)、Pd(dppf)Cl2(0.5mmol) with 4-bromopyridine-2 (1H)-one (11.0mmol), 0.5mL is then added Water, 110 DEG C are stirred overnight.Question response terminates, and reaction system kieselguhr filters, and filtrate is spin-dried for, then extracts with DCM.Close And organic facies, then anhydrous Na2SO4Being dried, filter, rotation is steamed, and crude product silica gel column chromatography separates (DCM:MeOH=20:1), To 6-Amino-N-benzyl-2'-Oxy-1 ', 2'-dihydro-[3,4'-bis-pyridine]-5-Methanamide, white solid, productivity 75%.
m.p.253-255℃；1H NMR (500MHz, DMSO) δ 11.48 (s, 1H), 9.02 (d, J=7.8Hz, 1H), 8.50 (d, J=2.3Hz, 1H), 8.32 (d, J=2.3Hz, 1H), 7.40 (dd, J=14.2,7.1Hz, 5H), 7.33 (t, J= 7.7Hz, 2H), 7.26 (t, J=7.3Hz, 1H), 6.78 (d, J=1.6Hz, 1H), 6.65 (dd, J=6.9,1.8Hz, 1H), 4.51 (d, J=5.8Hz, 2H)；HRMS(ESI):m/z calcd for C18H16N4O2[M+H]+:321.1346,Found: 321.1348.
Embodiment 36:6-Amino-N-benzyl-1'-methyl-2'-Oxy-1 ', 2'-dihydro-[3,4'-bis-pyridine]-5-first Amide
With reference to the method for embodiment 35, simply change 4-bromopyridine-2 (1H)-one into 4-bromo-1-methyl-2 (1H)-one, instead After should terminating, being evaporated to dry obtain crude product, obtain brown solid through column chromatography purification (DCM/MeOH=20:1), yield is 67%.
m.p.240-243℃；1H NMR (500MHz, DMSO) δ 9.22 (t, J=5.8Hz, 1H), 8.52 (d, J= 2.2Hz, 1H), 8.36 (d, J=2.2Hz, 1H), 7.72 (d, J=7.2Hz, 1H), 7.53 (s, 2H), 7.33 (d, J=4.4Hz, 4H), 7.24 (dd, J=8.7,4.4Hz, 1H), 6.79 (d, J=1.8Hz, 1H), 6.65 (dd, J=7.1,2.0Hz, 1H), 4.48 (d, J=5.8Hz, 2H), 3.41 (s, 3H)；HRMS(ESI):m/z calcd for C19H18N4O2[M+H]+: 335.1503,Found:335.1508.
Embodiment 37:6-amino-N, 1' dibenzyl-2'-Oxy-1 ', 2'-dihydro-[3,4'-bis-pyridine]-5-Methanamide
With reference to the method for embodiment 35, simply change 4-bromopyridine-2 (1H)-one into 1-benzyl-4-bromo-2 (1H)-one, instead After should terminating, being evaporated to dry obtain crude product, obtain yellow solid through column chromatography purification (DCM/MeOH=20:1), yield is 58%.
m.p.199-201℃；1H NMR (500MHz, DMSO) δ 9.22 (t, J=5.8Hz, 1H), 8.55 (d, J= 2.3Hz, 1H), 8.39 (d, J=2.3Hz, 1H), 7.85 (d, J=7.2Hz, 1H), 7.55 (s, 2H), 7.41 7.04 (m, 10H), 6.85 (d, J=2.0Hz, 1H), 6.72 (dd, J=7.2,2.1Hz, 1H), 5.09 (d, J=35.5Hz, 2H), 4.50 (d, J=5.8Hz, 2H)；HRMS(ESI):m/z calcd for C25H22N4O2[M+H]+:411.1816,Found: 411.1809.
Embodiment 38:6-amino-N-(2,6-difluorobenzyl)-2'-Oxy-1 ', 2'-dihydro-[3,4'-bis-pyridine]-5- Methanamide
With reference to the method for embodiment 35, simply change 2-Amino-N-benzyl-5-bromine nicotiamide into the 2-bromo-N-of amino-5- (2,6-difluorobenzyl) nicotiamide, after reaction terminates, is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH= 20:1) obtaining white solid, yield is 52%.
m.p.290-292℃；1H NMR (500MHz, DMSO) δ 11.47 (s, 1H), 9.07 (t, J=4.8Hz, 1H), 8.49 (d, J=2.1Hz, 1H), 8.26 (d, J=2.0Hz, 1H), 7.48 (s, 2H), 7.45 7.36 (m, 2H), 7.12 (t, J= 7.9Hz, 2H), 6.69 (s, 1H), 6.57 (d, J=6.9Hz, 1H), 4.53 (d, J=4.9Hz, 2H)；HRMS(ESI):m/z calcd for C18H14F2N4O2[M+H]+:357.1158,Found:357.1150.
Embodiment 39:6-amino-N-(4-methoxyphenyl)-2'-Oxy-1 ', 2'-dihydro-[3,4'-bis-pyridine]-5- Methanamide, with reference to the method for embodiment 35, simply changes 2-Amino-N-benzyl-5-bromine nicotiamide into 2-amine-5-bromo-N-(4-first Phenyl) nicotiamide, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH=20:1) Obtaining white solid, yield is 60%.
m.p.272-274℃；1H NMR (500MHz, DMSO) δ 11.48 (s, 1H), 10.19 (s, 1H), 8.51 (d, J= 2.2Hz, 1H), 8.36 (d, J=2.2Hz, 1H), 7.56 (d, J=9.0Hz, 2H), 7.44 7.26 (m, 3H), 6.93 (d, J= 9.0Hz, 2H), 6.73 (d, J=1.5Hz, 1H), 6.62 (dd, J=6.9,1.6Hz, 1H), 3.74 (s, 3H)；HRMS(ESI): m/z calcd for C18H16N4O2[M+H]+:337.1295,Found:337.1298.
Embodiment 40:6-amino-2'-epoxide-N-phenyl-1', 2'-dihydro-[3,4'-bis-pyridine]-5-Methanamide
With reference to the method for embodiment 35, simply change 2-Amino-N-benzyl-5-bromine nicotiamide into 2-amino-5-bromo-N-benzene Base nicotiamide, after reaction terminates, is evaporated to dry obtain crude product, obtains yellow through column chromatography purification (DCM/MeOH=20:1) Solid, yield is 70%.
m.p.256-257℃；1H NMR (500MHz, DMSO) δ 11.50 (s, 1H), 10.30 (s, 1H), 8.53 (d, J= 2.3Hz, 1H), 8.37 (d, J=2.3Hz, 1H), 7.73 7.61 (m, 2H), 7.41 (d, J=6.9Hz, 1H), 7.36 (dd, J= 9.6,6.2Hz, 4H), 7.12 (t, J=7.4Hz, 1H), 6.74 (d, J=1.6Hz, 1H), 6.62 (dd, J=6.9,1.8Hz, 1H)；HRMS(ESI):m/z calcd for C17H14N4O2[M+H]+:307.1190,Found:307.1195.
Embodiment 41:6-amino-N-(4-fluorophenyl)-2'-Oxy-1 ', 2'-dihydro-[3,4'-bis-pyridine]-5-formyl Amine
With reference to the method for embodiment 35, simply change 2-Amino-N-benzyl-5-bromine nicotiamide into the 2-bromo-N-of amino-5- (4-fluorophenyl) nicotiamide, after reaction terminates, is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH=20:1) Obtaining yellow solid, yield is 70%.
m.p.259-261℃；1H NMR (500MHz, DMSO) δ 11.50 (s, 1H), 10.35 (s, 1H), 8.53 (d, J= 2.3Hz, 1H), 8.37 (d, J=2.3Hz, 1H), 7.73 7.65 (m, 2H), 7.41 (d, J=6.9Hz, 1H), 7.37 (s, 2H), 7.20 (dd, J=15.1,6.2Hz, 2H), 6.73 (d, J=1.5Hz, 1H), 6.62 (dd, J=6.9,1.7Hz, 1H)；HRMS (ESI):m/z calcd for C17H13FN4O2[M+H]+:325.1095,Found:325.1093.
Embodiment 42:6-amino-2'-epoxide-N-(1-phenylethyl)-1', 2'-dihydro-[3,4'-bis-pyridine]-5-first Amide
With reference to the method for embodiment 35, simply change 2-Amino-N-benzyl-5-bromine nicotiamide into the 2-bromo-N-of amino-5- (1-phenylethyl) nicotiamide, after reaction terminates, is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH=20: 1) obtaining gray solid, yield is 61%.
m.p.252-253℃；1H NMR (500MHz, DMSO) δ 11.50 (s, 1H), 8.98 (d, J=7.8Hz, 1H), 8.50 (d, J=2.3Hz, 1H), 8.37 (d, J=2.3Hz, 1H), 7.42 (dd, J=14.2,7.1Hz, 5H), 7.35 (t, J= 7.7Hz, 2H), 7.24 (t, J=7.3Hz, 1H), 6.77 (d, J=1.6Hz, 1H), 6.62 (dd, J=6.9,1.8Hz, 1H), 5.35 4.97 (m, 1H), 1.51 (d, J=7.1Hz, 3H)；HRMS(ESI):m/z calcd for C19H18N4O2[M+H]+: 335.1503,Found:335.1508.
Embodiment 43:6-amino-1'-methyl-2'-epoxide-(1-phenylethyl)-1', 2'-dihydro-[3,4'-bis-pyrrole Pyridine]-5-Methanamide
With reference to the method for embodiment 36, simply change 2-Amino-N-benzyl-5-bromine nicotiamide into the 2-bromo-N-of amino-5- (1-phenylethyl) nicotiamide, after reaction terminates, is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH=20: 1) obtaining black solid, yield is 66%.
m.p.100-101℃；1H NMR (500MHz, DMSO) δ 8.96 (t, J=9.3Hz, 1H), 8.53 (d, J= 2.3Hz, 1H), 8.39 (d, J=2.3Hz, 1H), 7.75 (d, J=7.1Hz, 1H), 7.45 (s, 2H), 7.41 (d, J=7.4Hz, 2H), 7.35 (t, J=7.7Hz, 2H), 7.24 (t, J=7.2Hz, 1H), 6.87 (d, J=1.9Hz, 1H), 6.69 (dd, J= 7.1,2.0Hz, 1H), 5.19 (p, J=7.1Hz, 1H), 3.45 (s, 3H), 1.52 (d, J=7.1Hz, 3H)；HRMS(ESI):m/ z calcd for C20H20N4O2[M+H]+:349.1659,Found:349.1659.
Embodiment 44:6-amino-1'-benzyl-2'-epoxide-N-(1-phenylethyl)-1', 2'-dihydro-[3,4'-bis-pyrrole Pyridine]-5-Methanamide
With reference to the method for embodiment 37, simply change 2-Amino-N-benzyl-5-bromine nicotiamide into the 2-bromo-N-of amino-5- (1-phenylethyl) nicotiamide, after reaction terminates, is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH=20: 1) obtaining white solid, yield is 59%.
m.p.267-270℃；1H NMR (500MHz, DMSO) δ 8.95 (d, J=7.8Hz, 1H), 8.53 (d, J= 2.3Hz, 1H), 8.39 (d, J=2.3Hz, 1H), 7.86 (d, J=7.2Hz, 1H), 7.46 (s, 2H), 7.40 (d, J=7.5Hz, 2H), 7.33 (tdd, J=11.8,7.6,4.3Hz, 7H), 7.24 (t, J=7.3Hz, 1H), 6.89 (d, J=2.0Hz, 1H), 6.73 (dd, J=7.2,2.1Hz, 1H), 5.14 (s, 2H), 1.51 (d, J=7.1Hz, 3H)；HRMS(ESI):m/z calcd for C26H24N4O2[M+H]+:425.1972,Found:425.1972.
Embodiment 45:6-amino-N-(1-(2,6-bis-chloro-3-fluorophenyl) ethyl)-2'-Oxy-1 ', 2'-dihydro-[3, 4'-bis-pyridine]-5-Methanamide
With reference to the method for embodiment 35, simply change 2-Amino-N-benzyl-5-bromine nicotiamide into the 2-bromo-N-of amino-5- (1-(2,6-bis-chloro-3-fluorophenyl) ethyl) nicotiamide, after reaction terminates, is evaporated to dry obtain crude product, pure through column chromatography Changing (DCM/MeOH=20:1) and obtain gray solid, yield is 69%.
m.p.288-290℃；1H NMR (500MHz, DMSO) δ 11.52 (s, 1H), 9.23 (d, J=5.0Hz, 1H), 8.48 (s, 1H), 8.40 (d, J=13.0Hz, 1H), 7.50 7.45 (m, 1H), 7.42 (d, J=6.8Hz, 1H), 7.34 (dd, J =17.3,8.6Hz, 3H), 6.75 (s, 1H), 6.59 (d, J=6.5Hz, 1H), 5.69-5.54 (m, 1H), 1.60 (d, J= 7.3Hz,3H)；HRMS(ESI):m/z calcd for C19H15Cl2FN4O2[M+H]+:421.0629,Found:421.0627.
Embodiment 46:6-amino-N-(1-(2,6-bis-chloro-3-fluorophenyl) ethyl)-1'-methyl-2'-Oxy-1 ', 2'- Dihydro-[3,4'-bis-pyridine]-5-Methanamide
With reference to the method for embodiment 36, simply change 2-Amino-N-benzyl-5-bromine nicotiamide into the 2-bromo-N-of amino-5- (1-(2,6-bis-chloro-3-fluorophenyl) ethyl) nicotiamide, after reaction terminates, is evaporated to dry obtain crude product, pure through column chromatography Changing (DCM/MeOH=20:1) and obtain yellow solid, yield is 74%.
m.p.290-293℃；1H NMR (500MHz, DMSO) δ 9.23 (d, J=5.3Hz, 1H), 8.52 (d, J= 2.3Hz, 1H), 8.42 (d, J=2.3Hz, 1H), 7.76 (d, J=7.1Hz, 1H), 7.48 (dd, J=8.9,5.0Hz, 1H), 7.36 (dd, J=15.0,6.1Hz, 3H), 6.87 (d, J=1.9Hz, 1H), 6.68 (dd, J=7.1,2.0Hz, 1H), 5.71 5.58 (m, 1H), 3.45 (s, 3H), 1.63 (d, J=7.4Hz, 3H)；HRMS(ESI):m/z calcd for C20H17Cl2FN4O2[M+H]+:435.0785,Found:435.0783.
Embodiment 47:6-amino-1'-benzyl-N-(1-(2,6-bis-chloro-3-fluorophenyl) ethyl)-2'-Oxy-1 ', 2'- Dihydro-[3,4'-bis-pyridine]-5-Methanamide
With reference to the method for embodiment 37, simply change 2-Amino-N-benzyl-5-bromine nicotiamide into the 2-bromo-N-of amino-5- (1-(2,6-bis-chloro-3-fluorophenyl) ethyl) nicotiamide, after reaction terminates, is evaporated to dry obtain crude product, pure through column chromatography Changing (DCM/MeOH=20:1) and obtain white solid, yield is 62%.
m.p.275-277℃；1H NMR (500MHz, DMSO) δ 9.20 (d, J=5.2Hz, 1H), 8.51 (dd, J=9.1, 2.1Hz, 1H), 8.42 (t, J=6.7Hz, 1H), 7.85 (d, J=7.2Hz, 1H), 7.52 7.42 (m, 1H), 7.31 (tt, J= 19.6,7.9Hz, 8H), 6.88 (t, J=4.7Hz, 1H), 6.75 6.64 (m, 1H), 5.67 5.54 (m, 1H), 5.12 (s, 2H), 1.60 (d, J=7.4Hz, 3H)；HRMS(ESI):m/z calcd for C26H21Cl2FN4O2[M+H]+:511.1098, Found:511.1098.
Embodiment 48:(R)-6-amino-5-((1-(2,6-bis-chloro-3-fluorophenyl) ethyl) sulfenyl)-[3,4'-bis-pyrrole Pyridine]-2'(1'H)-one
(R) the bromo-3-of-5-((1-(2,6-bis-chloro-3-fluorophenyl) ethyl) sulfenyl) pyridine-2-amine and connection boric acid pinacol ester (11.0mmol) it is dissolved in 20mL anhydrous dioxane with potassium acetate (15.0mmol), is subsequently adding Pd (dppf) Cl2 (0.5mmol), nitrogen is replaced, and 80 DEG C of heating 8h, LC-MS monitoring reactions treat that raw material disappears.Question response natural cooling, does not separates, Cesium carbonate (15.0mmol), Pd (dppf) Cl is added the most again in reaction system2(0.5mmol) and 4-bromopyridine-2 (1H)- Ketone (11.0mmol), then adds 0.5mL water, and 110 DEG C are stirred overnight.Question response terminates, and reaction system kieselguhr filters, Filtrate is spin-dried for, then extracts with DCM.Merge organic facies, then anhydrous Na2SO4Being dried, filter, rotation is steamed, crude product silicagel column Chromatography (PE:EA=10:1), obtain (R)-6-amino-5-((1-(2,6-bis-chloro-3-fluorophenyl) ethyl) sulfenyl)-[3, 4'-bis-pyridine]-2'(1'H)-one, yellow solid, productivity 75%.
m.p.230-233℃；1H NMR (500MHz, DMSO) δ 11.44 (s, 1H), 8.32 (s, 1H), 7.46 (dd, J= 17.6,2.0Hz, 1H), 7.38 7.32 (m, 2H), 6.64 (d, J=5.0Hz, 2H), 6.39 6.14 (m, 2H), 5.07 (d, J= 7.2Hz,1H),2.09-1.64(m,3H)；HRMS(ESI):m/z calcd for C18H14Cl2FN3OS[M+H]+: 410.0291,Found:410.0296.
Embodiment 49:(R)-6-amino-5-((1-(2,6-bis-chloro-3-fluorophenyl) ethyl) sulfenyl)-1'-methyl [3,4'- Two pyridines]-2'(1'H)-one
With reference to the method for embodiment 48, simply change 4-bromopyridine-2 (1H)-one into 4-bromo-1-methyl-2 (1H)-one, instead After should terminating, being evaporated to dry obtain crude product, obtain yellow solid through column chromatography purification (PE/EA=5:1), yield is 77%.
m.p.194-197℃；1H NMR (500MHz, DMSO) δ 8.34 (dd, J=3.6,2.5Hz, 1H), 7.67 (d, J= 7.1Hz, 1H), 7.50 (dd, J=15.7,2.4Hz, 1H), 7.36 (dt, J=9.6,2.9Hz, 1H), 6.65 (s, 2H), 6.37 (ddd, J=8.3,7.3,1.6Hz, 2H), 5.12 5.01 (m, 1H), 3.40 (d, J=0.9Hz, 3H), 1.81 (dd, J=7.4, 1.9Hz,3H)；HRMS(ESI):m/z calcd for C19H16Cl2FN3OS[M+H]+:424.0448,Found:424.0446.
Embodiment 50:(R)-6-amino-1'-benzyl-5-((1-(2,6-bis-chloro-3-fluorophenyl) ethyl) sulfenyl)-[3, 4'-bis-pyridine]-2'(1'H)-one
With reference to the method for embodiment 48, simply change 4-bromopyridine-2 (1H)-one into 1-benzyl-4-bromo-2 (1H)-one, instead After should terminating, being evaporated to dry obtain crude product, obtain yellow solid through column chromatography purification (PE/EA=5:1), yield is 67%.
m.p.64-68℃；1H NMR(500MHz,CDCl3) δ 8.28 (t, J=2.2Hz, 1H), 7.64 (d, J=2.3Hz, 1H), 7.38 7.30 (m, 6H), 7.02 (dd, J=8.8,8.0Hz, 1H), 6.63 (dd, J=9.3,1.9Hz, 1H), 6.26 (td, J=7.1,2.1Hz, 1H), 5.48 (d, J=5.0Hz, 2H), 5.17 (s, 2H), 5.06 (ddt, J=8.8,7.4, 4.4Hz, 1H), 1.86 (dd, J=7.3,4.8Hz, 3H)；HRMS(ESI):m/z calcd for C25H20Cl2FN3OS[M+H ]+:500.0761,Found:500.0758.
Embodiment 51:(R)-6-amino-5-((1-(2,6-bis-chloro-3-fluorophenyl) ethyl) sulfenyl)-1'-(2-(dimethyl Amino) ethyl)-[3,4'-bis-pyridine]-2'(1'H)-one
With reference to the method for embodiment 48 into, simply 4-bromopyridine-2 (1H)-one is changed the bromo-1-of 4-(2-(dimethylamino) Ethyl) pyridine-2 (1H)-one, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography purification (PE/EA=5:1) To black solid, yield is 61%.
m.p.192-195℃；1H NMR (500MHz, DMSO) δ 8.34 (dd, J=3.6,2.5Hz, 1H), 7.61 (d, J= 7.1Hz, 1H), 7.50 (dd, J=13.3,2.4Hz, 1H), 7.43 7.23 (m, 2H), 6.63 (s, 2H), 6.40 6.28 (m, 2H), 5.12 5.01 (m, 1H), 3.95 (t, J=6.2Hz, 2H), 2.55 2.51 (m, 2H), 2.20 (s, 6H), 1.81 (dd, J =7.4,2.3Hz, 3H)；HRMS(ESI):m/z calcd for C22H23Cl2FN4OS[M+H]+:481.1026,Found: 481.1020.
Embodiment 52: ethyl (R)-2-(6-amino-5-((1-(2,6-bis-chloro-3-fluorophenyl) ethyl) sulfenyl)-2'-oxygen Base-[3,4'-pyridine]-1'(2'H)-yl) acetas
With reference to the method for embodiment 48 into, simply 4-bromopyridine-2 (1H)-one is changed ethyl 2-(4-bromo-2-oxy picolinate-1 (2H)-yl) acetas, after reaction terminates, it is evaporated to dry obtain crude product, obtains Huang through column chromatography purification (PE/EA=5:1) Color solid, yield is 57%.
m.p.66-69℃；1H NMR(500MHz,CDCl3)δ8.28(s,1H),7.66-7.63(m,1H,),7.54-7.48 (m, 1H), 7.48 7.43 (m, 1H), 7.24 (d, J=6.6Hz, 1H), 7.18 (dd, J=8.9,5.0Hz, 1H), 7.01 (t, J =8.4Hz, 1H), 6.58 (d, J=8.1Hz, 1H), 6.30 (t, J=7.2Hz, 1H), 5.47 (s, 2H), 5.09 5.01 (m, 1H), 4.66 (s, 2H), 4.26 (q, J=7.1Hz, 2H), 1.85 (dd, J=7.2,5.7Hz, 3H), 1.33-1.31 (m, 3H)； HRMS(ESI):m/z calcd for C22H20Cl2FN3O3S[M+H]+:496.0659,Found:496.0662.
Embodiment 53:(R)-6-amino-5-((1-(2,6-bis-chloro-3-fluorophenyl) ethyl) sulfenyl)-1'-ethyl-[3, 4'-bis-pyridine]-2'(1'H)-one
With reference to the method for embodiment 48, simply 4-bromopyridine-2 (1H)-one is changed into 4-bromo-1-ethylpyridine-2 (1H)- Ketone, after reaction terminates, is evaporated to dry obtain crude product, obtains yellow solid, yield through column chromatography purification (PE/EA=5:1) It is 69%.
m.p.145-148℃；1H NMR(500MHz,CDCl3) δ 8.26 (s, 1H), 7.63 (d, J=2.3Hz, 1H), 7.31 (dd, J=9.6,4.3Hz, 1H), 7.26 (s, 1H), 7.04 6.98 (m, 1H), 6.57 (dd, J=9.9,1.9Hz, 1H), 6.27 (td, J=7.6,2.0Hz, 1H), 5.39 (s, 2H), 5.09 5.01 (m, 1H), 4.12 (q, J=7.1Hz, 1H), 4.00 (q, J =7.2Hz, 2H), 1.85 (dd, J=7.3,5.0Hz, 2H), 1.38 (t, J=7.2Hz, 3H)；HRMS(ESI):m/z calcd for C20H18Cl2FN3OS[M+H]+:438.0604,Found:438.0601.
Karpas299, NCI-H2228, SKN-BE2 and SH-SY5Y cell inhibitory effect is lived by embodiment 54 compound Property measure
This example is used for measuring the compounds of this invention for ALK overexpression cell line Karpas299 (NPM-ALK positive cell Strain), NCI-H2228 (EML4-ALK positive cell strain), SKN-BE2 (ALK gene amplifying cells strain) and SH-SY5Y (ALK F1174 mutant clone) proliferation inhibition activity, compound on intracellular propagation inhibitory activity half-inhibition concentration IC50Come Represent.Testing program is as follows: ALK overexpression cell line Karpas299 (NPM-ALK positive cell strain), NCI-H2228 (EML4- ALK positive cell strain), SKN-BE2 (ALK gene amplifying cells strain) and SH-SY5Y (ALK F1174 mutant clone) all purchases In ATCC, with suitable cell concentration (20000 cell/ml culture medium), cell is inoculated in 384 hole trainings of White-opalescent Support on plate；Afterwards cell is positioned over 37 DEG C, 5%CO2Environment in cultivate, after 24 hours, to cultivate cell cultivate Base adds the medicine of a series of Concentraton gradient, is typically chosen 10 concentration, afterwards cell is put back in former culture environment and continue Cultivate 48 hours, afterwards according to the method for CellTiter-Glo Luminescent Cell Viability Assay, measure The test-compound impact on Karpas299, NCI-H2228, SKN-BE2 and SH-SY5Y cell proliferation, and calculate different dense The inhibitory activity of the compound on intracellular propagation of degree, CellTiter-Glo Luminescent Cell Viability Assay Detectable is purchased from Promega.Afterwards to Karpas299, NCI-H2228, SKN-BE2 under the compound of variable concentrations and SH-SY5Y cell inhibitory effect activity carries out four parameter fittings, the IC of test-compound50Data see table 1, table 2.
Table 1
Table 2
Conclusion: in the compound of these a series of present invention, part of compounds tumor cell Karpas299 in vitro (NPM-ALK positive cell strain), NCI-H2228 (EML4-ALK positive cell strain), SKN-BE2 (ALK gene amplifying cells strain) And it is suitable with positive Crizotinib in the cell growth inhibition assay of SH-SY5Y (ALK F1174 mutant clone).
In the compounds of this invention structure, there is novelty, be the new compound skeleton proposed first, external biological simultaneously Activity evaluation shows, the compound of present invention Karpas299 (NPM-ALK positive cell strain), NCI-to process LAN ALK (ALK F1174 suddenlys change for H2228 (EML4-ALK positive cell strain), SKN-BE2 (ALK gene amplifying cells strain) and SH-SY5Y Cell strain) there is obvious proliferation inhibition activity, part of compounds is suitable with positive Crizotinib, presses down for design new A LK Preparation provides mentality of designing.

Claims (4)

1. the PA derivant containing 2-pyridone ring side chain or its enantiomer, it is characterised in that structure is led to Formulas I is as follows:
Wherein:
R1Selected from hydrogen, C1～C6Alkyl, C3～C6Ester group, C2～C6Chain amino, C1～C2The substituted C of alkyl2～C6Chain amino, tertiary fourth The substituted C of oxygen carbonyl2～C6Chain amino；
R2For hydrogen, methyl；
R3For replacing or unsubstituted phenyl and substituted or unsubstituted heteroaryl, described is substituted by by C1～C6Alkyl, Halogen, C1～C6One or more in alkyl oxy, cyano group, trifluoromethyl are replaced；
X takes from hydrogen, oxygen, sulfur or amide.
A kind of PA derivant containing 2-pyridone ring the most according to claim 1 or its enantiomer, its It is characterised by: described compound of formula I is following arbitrary compound:
6-amino-[3,4'-bis-pyridine]-2'(1'H)-one (compound 1)；
6-amino-1'-methyl-[3,4'-bis-pyridine]-2'(1'H)-one (compound 2)；
6-amino-1'-benzyl-[3,4'-bis-pyridine]-2'(1'H)-one (compound 3)；
6-amino-1'-(2-(dimethylamino) ethyl)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 4)；
6-amino-5-(benzyloxy)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 5)；
6-amino-5-(benzyloxy)-1'-methyl-[3,4'-bis-pyridine]-2'(1'H)-one (compound 6)；
6-amino-5-(benzyloxy)-1'-benzyl-[3,4'-bis-pyridine]-2'(1'H)-one (compound 7)；
6-amino-5-(benzyloxy)-1'-(2-(dimethylamino) ethyl)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 8)；
6-amino-5-((2,6-difluorobenzyl) oxo)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 9)；
6-amino-5-((2,6-difluorobenzyl) oxo)-1'-methyl-[3,4'-bis-pyridine]-2'(1'H)-one (compound 10)；
6-amino-5-((2,6-difluorobenzyl) oxo)-1'-benzyl-[3,4'-bis-pyridine]-2'(1'H)-one (compound 11)；
6-amino-5-((2,6-difluorobenzyl) oxo)-1'-(2-(dimethylamino) ethyl)-[3,4'-bis-pyridine]-2'(1' H)-one (compound 12)；
6-amino-5-(1-phenyl ethoxy)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 13)；
6-amino-1'-methyl-5-(1-phenyl ethoxy)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 14)；
6-amino-5-(1-(p-methylphenyl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 15)；
6-amino-1'-methyl-5-(1-(p-methylphenyl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 16)；
6-amino-5-(1-(4-chlorphenyl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 17)；
6-amino-1'-methyl-5-(1-(4-chlorphenyl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 18)；
6-amino-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 19)；
6-amino-1'-methyl-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 20)；
6-amino-1'-benzyl-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 21)；
6-amino-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-1'-(2-(dimethylamino) ethyoxyl)-[3,4'-bis- Pyridine]-2'(1'H)-one (compound 22)；
6-amino-1'-methyl-5-(1-pyridine-2-base) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 23)；
6-amino-1'-methyl-5-(1-pyridin-3-yl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 24)；
6-amino-1'-methyl-5-(1-pyridin-4-yl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 25)；
(R)-6-amino-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)-one (chemical combination Thing 26)；
(R)-6-amino-1'-methyl-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)- Ketone (compound 27)；
(R)-6-amino-1'-benzyl-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)- Ketone (compound 28)；
(R)-6-amino-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-1'-(2-(dimethylamino) ethyoxyl)-[3, 4'-bis-pyridine]-2'(1'H)-one (compound 29)；
(R)-6-amino-1'-ethyl-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)- Ketone (compound 30)；
Ethyl-(R)-2-(6-amino-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-2'-epoxide-[3,4'-bis-pyridine]- 1'(2'H)-yl) acetas (compound 31)；
(R)-6-amino-1'-propyl group-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis-pyridine]-2'(1'H)- Ketone (compound 32)；
6-Amino-N-benzyl-2'-Oxy-1 ', 2'-dihydro-[3,4'-bis-pyridine]-5-Methanamide (compound 33)；
6-Amino-N-benzyl-1'-methyl-2'-Oxy-1 ', 2'-dihydro-[3,4'-bis-pyridine]-5-Methanamide (compound 34)；
6-amino-N, 1' dibenzyl-2'-Oxy-1 ', 2'-dihydro-[3,4'-bis-pyridine]-5-Methanamide (compound 35)；
6-amino-N-(2,6-difluorobenzyl)-2'-Oxy-1 ', 2'-dihydro-[3,4'-bis-pyridine]-5-Methanamide (compound 36)；
6-amino-N-(4-methoxyphenyl)-2'-Oxy-1 ', 2'-dihydro-[3,4'-bis-pyridine]-5-Methanamide (compound 37)；
6-amino-2'-epoxide-N-phenyl-1', 2'-dihydro-[3,4'-bis-pyridine]-5-Methanamide (compound 38)；
6-amino-N-(4-fluorophenyl)-2'-Oxy-1 ', 2'-dihydro-[3,4'-bis-pyridine]-5-Methanamide (compound 39)；
6-amino-2'-epoxide-N-(1-phenylethyl)-1', 2'-dihydro-[3,4'-bis-pyridine]-5-Methanamide (compound 40)；
6-amino-1'-methyl-2'-epoxide-(1-phenylethyl)-1', 2'-dihydro-[3,4'-bis-pyridine]-5-Methanamide (is changed Compound 41)；
6-amino-1'-benzyl-2'-epoxide-N-(1-phenylethyl)-1', 2'-dihydro-[3,4'-bis-pyridine]-5-Methanamide (compound 42)；
6-amino-N-(1-(2,6-bis-chloro-3-fluorophenyl) ethyl)-2'-Oxy-1 ', 2'-dihydro-[3,4'-bis-pyridine]-5- Methanamide (compound 43)；
6-amino-N-(1-(2,6-bis-chloro-3-fluorophenyl) ethyl)-1'-methyl-2'-Oxy-1 ', 2'-dihydro-[3,4'-bis- Pyridine]-5-Methanamide (compound 44)；
6-amino-1'-benzyl-N-(1-(2,6-bis-chloro-3-fluorophenyl) ethyl)-2'-Oxy-1 ', 2'-dihydro-[3,4'-bis- Pyridine]-5-Methanamide (compound 45)；
(R)-6-amino-5-((1-(2,6-bis-chloro-3-fluorophenyl) ethyl) sulfenyl)-[3,4'-bis-pyridine]-2'(1'H)-one (compound 46)；
(R)-6-amino-5-((1-(2,6-bis-chloro-3-fluorophenyl) ethyl) sulfenyl)-1'-methyl [3,4'-bis-pyridine]-2'(1' H)-one (compound 47)；
(R)-6-amino-1'-benzyl-5-((1-(2,6-bis-chloro-3-fluorophenyl) ethyl) sulfenyl)-[3,4'-bis-pyridine]-2' (1'H)-one (compound 48)；
(R)-6-amino-5-((1-(2,6-bis-chloro-3-fluorophenyl) ethyl) sulfenyl)-1'-(2-(dimethylamino) ethyl)- [3,4'-bis-pyridine]-2'(1'H)-one (compound 49)；
Ethyl (R)-2-(6-amino-5-((1-(2,6-bis-chloro-3-fluorophenyl) ethyl) sulfenyl)-2'-epoxide-[3,4'-pyrrole Pyridine]-1'(2'H)-yl) acetas (compound 50)；
(R)-6-amino-5-((1-(2,6-bis-chloro-3-fluorophenyl) ethyl) sulfenyl)-1'-ethyl-[3,4'-bis-pyridine]-2' (1'H)-one (compound 51)；
The tert-butyl group-(R)-(2-(6-amino-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-2'-oxygen-[3,4'-bis-pyrrole Pyridine]-1'(2'H)-yl) ethyl) carboxylate (compound 52)；
(R)-6-amino-1'-(2-amino-ethyl)-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-[3,4'-bis-pyridine]- 2'(1'H)-one (compound 53).
PA derivant containing 2-pyridone ring the most according to claim 1 and 2 or the system of its enantiomer Preparation Method, it is characterised in that realized by following steps:
(1) compound A: under condition of ice bath, raw material PA I and ammonium acetate stir 10min, the most in batches in acetonitrile Add N-bromosuccinimide, after N-bromosuccinimide adds, be stirred for half an hour under the same conditions, obtain bromine For product 5-bromo-PA II, under anhydrous and oxygen-free operating condition, 5-bromo-PA II and connection boric acid pinacol Ester and potassium acetate occur boration effect to generate (6-aminopyridine-3-base) boric acid under palladium catalyst catalytic action, and LC-MS supervises After measured reaction terminates, use " one kettle way ", directly put into the intermediate 2-pyridone III containing substituent group with appropriate to reaction system Palladium catalyst and cesium carbonate, 110 DEG C are stirred overnight, and finally give target compound A；Reaction equation:
Wherein the definition of substituent group is with claim 1, reagent and reaction condition: a) acetonitrile, 0 DEG C, 0.5h；B) 1,4-dioxy six Ring, 80 DEG C；C) Isosorbide-5-Nitrae-dioxane, 110 DEG C, 10h；
(2) compound B: with 1-Phenylethanone. IV as initiation material, with methanol as solvent, is repeatedly dividedly in some parts boron under condition of ice bath on a small quantity Sodium hydride, is then gradually brought to room temperature, generates 1-phenethanol V after reaction 2h.Under condition of ice bath, 1-phenethanol V is dissolved in In the oxolane being dried, it is subsequently added 2-hydroxy-3-nitropyridine VI and triphenylphosphine, then carries out nitrogen protection, DEAD Dropwise it is slowly added in reaction system, drips complete rear chamber temperature and be stirred overnight, obtain 2-nitro-3-(1-ethoxyphenyl) pyridine VII, 2-nitro-3-(1-ethoxyphenyl) pyridine VII obtains 3-(1-ethoxyphenyl) pyridine-2-amine VIII, 3-through iron powder reducing (1-ethoxyphenyl) pyridine-2-amine VIII generates the bromo-3-of 5-(1-ethoxyphenyl) pyrrole through NBS (N-bromosuccinimide) bromo Pyridine-2-amine IX, under anhydrous and oxygen-free operating condition, the bromo-3-of 5-(1-ethoxyphenyl) pyridine-2-amine IX and connection boric acid pinacol ester Boration effect is occurred to generate (6-amino-5-(1-ethoxyphenyl) pyridine-3-under palladium catalyst catalytic action with potassium acetate Base) boric acid, after LC-MS monitoring reaction terminates, use " one kettle way ", directly put into the 2-pyridine containing substituent group to reaction system Ketone III and appropriate palladium catalyst and cesium carbonate, 110 DEG C are stirred overnight, and finally give target compound B；Reaction equation:
Wherein the definition of substituent group is with claim 1, reagent and reaction condition: a) methanol, 0 DEG C of-rt, 2h；B) oxolane, 0 DEG C, 4h；C) ethanol, backflow, 1h, d) acetonitrile, 0 DEG C, 15min；E) Isosorbide-5-Nitrae-dioxane, 110 DEG C, 8h；F) Isosorbide-5-Nitrae-dioxane, 110 DEG C, 10h；
(3) compound C: under condition of ice bath, 1-phenethanol V and triethylamine are dissolved in dry dichloromethane, mesyl chloride by It is added dropwise to, progressively recovers to room temperature after treating mesyl chloride dropping, be then stirred overnight and obtain 1-phenethyl methanesulfonates X, 1-phenethyl methanesulfonates X obtains (1-azidoethyl) benzene XI, (1-azidoethyl) benzene XI through Azide and issues in zinc powder effect Former 1-phenethylamine XII, 1-phenethylamine XII and the 2-amino-5-bromo-nicotinic acid of obtaining of surviving is under HATU and DIPEA effect, in DMF Condensation reaction is occurred to generate the 2-bromo-N-of amino-5-(1-phenethyl) nicotiamide XIII, under the conditions of anhydrous and oxygen-free, 2-amino-5- Boric acid is there is in bromo-N-(1-phenethyl) nicotiamide XIII, potassium acetate and connection boric acid pinacol ester under palladium catalyst catalytic action Change reaction, generate (6-amino-5-((1-phenethyl) carbamyl) pyridin-3-yl) boric acid, use " one kettle way ", treat LC-MS After monitoring reaction completes, directly put into intermediate 2-pyridone III and appropriate palladium catalyst and cesium carbonate to reaction system, 110 DEG C are stirred overnight, and have finally given target compound C；Reaction equation:
Wherein the definition of substituent group is with claim 1, reagent and reaction condition: a) dichloromethane, 0 DEG C-room temperature, 10h；b)N,N- Dimethylformamide, 50 DEG C, 8h；C) ethanol/water of volume ratio 3:1, room temperature, 3h, d) DMF, 0 DEG C, room Temperature, 8h；E) Isosorbide-5-Nitrae-dioxane, 80 DEG C, 8h；F) Isosorbide-5-Nitrae-dioxane, 100 DEG C, 10h；
(4) compound D: at ambient temperature, 2-nitro-3-pyridone VI and dimethylamino sulfur acute pyogenic infection of nails acyl chlorides are DABCO's Generating O-(2-nitropyridine-3-base)-dimethylthiocarbamate XIV under effect, make solvent with diphenyl ether, 160 DEG C high Under the conditions of temperature, O-(2-nitropyridine-3-base)-dimethylthiocarbamate XIV becomes S-(2-nitropyridine-3-base)-two Methyl thio carbamate XV, S-(2-nitropyridine-3-base)-dimethylthiocarbamate XV is in 1-phenethanol effect Lower generation substitution reaction generates 2-nitro-3-((1-phenethyl) sulfur generation) pyridine XVI, 2-nitro-3-((1-phenethyl) sulfur generation) Pyridine XVI generates 3-((1-phenethyl) sulfur generation) pyridine-2-amine XVII, 3-((1-phenethyl) sulfur generation) pyrrole through iron powder reducing Pyridine-2-amine XVII generates the bromo-3-of 5-((1-phenethyl) sulfur generation) pyridine-2-amine XVIII through bromo, under the conditions of anhydrous and oxygen-free The bromo-3-of 5-((1-phenethyl) sulfur generation) pyridine-2-amine XVIII, potassium acetate are made in palladium catalyst catalysis with connection boric acid pinacol ester React with lower generation boration, generate (6-amino-5-((1-phenethyl) sulfur generation) pyridin-3-yl) boric acid, use " one pot Method ", after until LC-MS monitoring, reaction completes, directly to reaction system put into intermediate 2-pyridone III and appropriate palladium catalyst with And cesium carbonate, 110 DEG C are stirred overnight, and finally give target compound D；Reaction equation:
Wherein the definition of substituent group is with claim 1, reagent and reaction condition: a) DMF, room temperature, 24h；b) 160 DEG C, 3h；C) potassium hydroxide, volume ratio is the methanol/oxolane/water of 2:1:1,0 DEG C-room temperature；D) ethanol, backflow；E) bromine Element, potassium carbonate, dichloromethane, 0 DEG C；F) Isosorbide-5-Nitrae-dioxane, 80 DEG C, 8h；G) Isosorbide-5-Nitrae-dioxane, 110 DEG C, 10h.
PA derivant containing 2-pyridone ring the most according to claim 1 and 2 and enantiomer are in preparation Application in antitumor cell medicine, it is characterised in that described tumor cell refers to the tumor that alk tyrosine kinase activity is relevant Cell: Karpas299NPM-ALK positive cell strain, NCI-H2228EML4-ALK positive cell strain, SKN-BE2ALK gene expand Increase cell strain and SH-SY5Y ALK F1174 mutant clone.
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